Unseeded and ranked no. 55 in the world entering the US Open, Isner defeated world no. 29 Victor Hănescu in the first round, which was his first win in a Grand Slam tournament since the 2007 US Open, ending a streak of six consecutive defeats. He then advanced to the third round, where he defeated world no. 5 and fellow American Andy Roddick in five sets for his first victory over Roddick, his first victory in a five-set match, and the first time he advanced past the third round of a Grand Slam tournament. He was then defeated in the fourth round by world no. 10 Fernando Verdasco in four sets. His US Open performance brought his ranking to a career-high no. 39.