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I'd like to nominate "A Confederacy of Dunces" by John Kennedy Toole and Walker Percy.
From Amazon Reviews:
A Confederacy of Dunces is an American comic masterpiece. John Kennedy Toole’s hero is one Ignatius J. Reilly, “huge, obese, fractious, fastidious, and a latter-day Gargantua, a Don Quixote of the French Quarter. His story bursts with wholly original character, denizens of New Orleans’ lower depths, incredibly true-to-life dialogue, and the zaniest series of high and low comic adventures” (Henry Kisor, Chicago Sun Times)
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