Isner appeared in the first round of the 2010 Davis Cup, where the United States was up against Serbia. In his two singles matches, he faced Serbia's team of world no. 2 Novak Djokovic and world no. 35 Viktor Troicki. He lost the first singles match against Troicki, but bounced back by winning the doubles match with Bob Bryan, as a replacement for food-poisoned Mike Bryan. In his second singles match, he lost to Djokovic, which enabled Serbia to defeat the United States.