Isner teamed up with Jack Sock to win his second Masters doubles title and fourth overall doubles title at the 2016 Shanghai Masters. Unseeded at the final regular tournament of the season, Isner would prevail against seeded players David Ferrer and Marin Čilić to reach his third Masters final and second final of the season at the 2016 BNP Paribas Masters in Paris. His semifinal victory allowed him to again finish the year as the no. 1 American for the fifth consecutive year and inside the top 20 for the seventh consecutive season. In the final, Isner lost to the newly crowned world no. 1 Andy Murray, thus leaving him titleless in singles for the first time since 2009.