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Dorothea Brooke is a young woman living with her uncle and sister in the small-but-growing town of Middlemarch, England in around 1830. She's got all the makings of a Victorian heroine: she's beautiful, intelligent, and generous. But she's also so idealistic, it's almost laughable. Her main ambition in life is to take on a noble project – so she marries a dried-up old scholar named Casaubon, thinking that helping him in his research will be the project she's after. Not so much. Dorothea quickly discovers that he cares more for his own scholarly pursuits than he does for her, but she can't do much about it (this is in the days before divorce was allowed for anything other than adultery or physical abuse).
Meanwhile, an idealistic young doctor named Tertius Lydgate moves to Middlemarch to set up a practice with his new-fangled ideas about medicine and science. But he encounters a lot of obstacles. First of all, most of the residents of Middlemarch have lived in the town for their whole lives, and they don't trust newcomers. Second, they don't trust new ideas, and Lydgate is all about scientific progress. Lydgate falls in love with Rosamond Vincy, the sister of one his patients, and marries her.
More unhappiness in marriage! Lydgate discovers that Rosamond is a superficial and selfish, and Rosamond learns that Lydgate will always be "married" to his work as a doctor. And then they run out of money because neither of them knows how to stick to a budget.
These two unhappy couples (the Lydgates and the Casaubons) are connected by Mr. Casaubon's young cousin, Will Ladislaw. Will is a handsome, young artist with a sparkling wit. Seriously, he sparkles. Lydgate finds Will to be sympathetic to his ideas about science and medicine, and since Will is an outsider in Middlemarch, too, they quickly become friends. Everyone seems to like Will. Especially Dorothea, who finds that he understands her in a way her husband doesn't. But don't worry – Dorothea's halfway to sainthood, and she's not about to cheat on her husband. The thing about marrying a much older man, though, is that they pass away and leave you free to remarry.
But there's a catch: Mr. Casaubon was always jealous of the friendly bond between his cousin, Will, and his wife. So Mr. Casaubon leaves a codicil in his will (basically a postscript) saying that Dorothea will lose all the money she's supposed to inherit from him if she remarries Will Ladislaw. Dorothea hadn't even thought about marrying Will until she reads the codicil. She thought they were just friends!
After some serious thinking, and some misunderstandings (Dorothea thinks that Will likes Rosamond), Dorothea and Will decide to get married. They live happily ever after, despite the fact that they forfeit the large inheritance from dead Mr. Casaubon. And Rosamond and Lydgate live unhappily ever after – or, until Lydgate dies at a tragically early age, leaving Rosamond free to marry someone who's more willing to cater to her whims.