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Bernard Langdon is close to earning his degree in medicine when his family finds itself in financial difficulties, forcing Langdon to interrupt his studies for a time in order to earn money with which to fund the rest of his degree. He therefore leaves Boston in order to teach at a school in a village in the area. One of his students is Elsie Venner, a seventeen year-old girl, who is avoided by her peers and keeps apart. Somehow, Elsie exerts a great fascination on Langdon, as there is something distinctly different about her with her strangeness and quick temper.

Elsie Venner is one of Oliver Wendell Holmes' "medicated novels", in which he explores a medical condition of a character. Holmes was teaching at Harvard Medical School when this book was published, and he chose to let a professor of medicine narrate the story. Elsie Venner is notable for its strong Boston local colour, being at the same time the book in which Holmes coined the term "Boston Brahmin".