I'm sure this has been beat to death, but I have not been here to witness it. haha
I like to believe its Moby-Dick. I just loved the style, the plot, etc. And Ahab's struggle really felt American; out there to conquer nature because of some unholy force within compelling him to sail against the tides of fate. Driven by a self-professed religion, never acknowledging failure as an option.
I've heard some people say, however, that the novel really doesn't portray the "American voice" because like other mid 19th century literature, it tries to immitate the British style. I wouldn't say so. The only American work that I have honestly thought to sound British was Stevenson's Dr. Jekyll and Mr. Hyde. I was shocked to find out Stevenson was American.
Huck Finn is supposed to be "the American voice" but I just can't bring myself to give it that title. That's mostly out of my dislike of Huck as a character.