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The Time Traveler's Wife begins with a prologue in which the main characters, Henry and Clare, introduce the nature of their relationship as a time traveler and a time traveler's wife. The alternating first-person perspectives set a precedent for the rest of the story, which largely follows the chronology of Clare's life but also takes us along for some of Henry's time-traveling adventures.
Clare and Henry meet at the Newberry Library in Chicago. She's a 20-year-old art student. He's a 28-year-old librarian. Clare is overjoyed to see Henry – she tells him she has known him since she was 6. Henry doesn't remember her but agrees to go out to dinner with her, amazed at how much he means to this "luminous creature." During dinner, Clare reveals to him that she knows about his time travel disorder and that they met for the first time when she was 6 years old and he was 43. She shows him a diary that holds all dates for his visits. Henry feels overwhelmed by all this information, but also finds himself very attracted to her. He asks Clare to pretend that this is a normal first date between two normal people. Clare apologizes for her fervor. She tells him about her family and he tells her about his.
After dinner, Henry brings Clare home to his messy bachelor apartment. Without much ado, Clare tells him that she wants to make love to him because, for her, this day has been years in the making. Henry wants to take his time, but indulges her request nonetheless. He senses that there's something special between them. In the morning, Clare discovers another woman's toiletries in the bathroom. Henry tells her that his relationship with that other woman is over.
Henry then recalls the first time he time traveled. It's his fifth birthday. His parents take him to the Field Museum of Natural History in Chicago. Later that night, he suddenly pops back in time to the museum. A 24-year-old version of Henry takes on the job of guiding him through this first experience. Older Henry explains to younger Henry that he's a time traveler, but that he needs to keep his travels a secret. During Henry's teenage years, his older version teaches him time travelers' tricks of survival, including stealing, breaking and entering, and running from the police.
The narration jumps to the first time 43-year-old Henry meets 6-year-old Clare in a meadow, not far from her family's house on Lake Michigan. He calls out to Clare from behind a bush, where he's trying to conceal himself because he's naked. Clare grudgingly hands him her picnic blanket so he can cover up. But Henry explains to Clare that he's a time traveler, so he can't take anything with him as he pops in and out of time because that would really mess things up in the world. He asks her to please bring him some clothes the next time he visits and names the date. Clare is torn between fascination and suspicion. She watches Henry disappear before her eyes. On the date given, Clare waits for Henry with old clothes from her dad. When he shows up, Clare warms up to Henry and tells him that she now believes his story.
Throughout her childhood, and into her teenage years, Clare spends a lot of time with 43-year-old Henry. Although Henry refuses to divulge details about Clare's future with him, he does share bits and pieces of Clare's future self and their relationship in his present. Clare realizes that her relationship with Henry has changed her life and makes her different from other people. In fact, her peers take her to be strange and wonder why she's not interested in boys their own age.
One morning, Clare wakes up to Henry calling her name. Outside she finds her father and brother in hunting gear, looking at an empty spot of grass that's flecked with blood. She sees Henry standing off the distance, waving at her, but she senses that something terrible has happened.
Clare's budding teenage hormones make her long for a sexual relationship with Henry –since she knows now that she'll marry Henry and will be with him in her future, she wonders what's the big deal about having some sex now too? Henry blocks her advances, but admits that he loves her.
During Christmas time, Clare hides Henry in the reading room of her parents' house. Henry hates Christmas because it marks the day of his mother's death. He explains to her that on the morning of Christmas Eve, when Henry was six years old, they got into a car accident on their way to pick up his father. Henry survived only because he time traveled. The police found him standing naked by the side of the road. Since then, he has traveled to the scene of his mother's death again and again, but all he can do is watch the tragedy unfold, helpless. Henry blames himself for her death and thinks he should have died too.
Back in the present, Clare invites Henry to have dinner at her apartment with her roommate Charisse and with Gomez, Charisse's boyfriend. Gomez disapproves of Clare's relationship with Henry because he has garnered the reputation of a womanizer and troublemaker in Chicago's club scene. Case in point: two weeks after the dinner, Gomez sees an older version of Henry beat up a guy in front of a club. Gomez then follows him as Henry breaks into a store to get some clothes. When Henry reveals to him that he's a time traveler, Gomez doesn't believe him until Henry disappears before his eyes. The experience convinces Gomez even more that Henry is the wrong guy for Clare. But Clare tells him that her future has chosen Henry and, even if she had a choice, it still would be Henry because she loves the guy.
Clare brings Henry to meet her family for Christmas. Shortly after, Henry proposes to Clare. Both families give their blessings to their marriage. During the wedding ceremony, Clare exchanges vows with an older version of Henry, because present Henry has time traveled.
The second part of the story begins with Henry and Clare's married life, marked by Henry's frequent absences. Clare now worries about him a bunch when he's gone. She also starts to feel trapped in their small apartment, unable to properly pursue her work as an artist. Henry decides to use his time traveling advantage to rig the Illinois Lottery and Clare wins $8 million. This allows them to move into a house with a large studio for Clare.
Henry tracks down Dr. Kendrick, his doctor-to-be. Henry explains to the man that he time travels involuntarily, a condition that will later becomes known as "Chrono-Impairment." He tells Kendrick that they will work together on solving his problem. Kendrick, too, doesn't believe him until he sees Henry disappear right in front of him.
Faced with Henry's frequent absences, Clare starts to wish for a baby, so that a part of Henry will stay with her when he's gone. They experiences six miscarriages, because Henry's condition appears to be hereditary, causing the babies to time travel and Clare's body to abort them. The miscarriages put a strain on Henry and Clare's relationship until, finally, Henry decides to get a vasectomy. A younger version of him, though, enables Clare to get pregnant again. Clare has a good feeling about this pregnancy. Traveling to the future, Henry meets his daughter-to-be, Alba, as a ten-year-old, confirming that they'll indeed have a child this time. Alba is a time traveler as well, but she has more control over her travels than her father does. She reveals to Henry that he died at the age of 43 when she was only 5. Henry keeps his impending death a secret from Clare.
One day, Clare finds Henry on the living room floor, back from his travels and with severe hypothermia. At the hospital, his feet have to be amputated above the ankle. Both Henry and Clare know that not being able to run now puts Henry in severe danger on his time travels.
Dr. Kendrick informs Henry that he won't be able to cure him, mainly because his disorder is too complex to figure out in Henry's lifetime. But he believes that Alba might have a chance at a normal life.
At a New Year's party after Henry's 43rd birthday, Henry senses that he will die soon. He spends his last moments with Clare before he time travels to a day in Clare's past where he accidentally gets shot by her brother Mark while he's out hunting.
Book 3 describes Clare's life after Henry's death. She finds a letter from Henry, urging her to stop waiting for him and to move on with her life. He mentions, however, that he believes that he once traveled to a time where he saw her as an old woman in the future, so Clare decides to wait for him. During the following years, Henry travels back frequently to spend time with Alba, but he never visits Clare. Finally, when Clare is 82 years old, Henry comes to see her again.