On July 31 at AT&T Park, in a 3–1 win over the Washington Nationals, Cain won his one-hundredth career game by tossing five no-hit innings on ninety-three pitches, making him the sixth pitcher in the San Francisco Era and the twenty-third pitcher in Giants franchise history to win at least one hundred games. Cain is the second Giant on the season to earn his one-hundredth career victory after teammate Johnny Cueto won his on April 26. Since , Cain was one of three starting pitchers in the starting rotation, along with Tim Lincecum and Madison Bumgarner, to win over one hundred games and strikeout over 1,500 batters. In that span, the San Francisco Giants are the only Major League team to accomplish both feats, according to NBC Sports Bay Area. The Giants franchise are the only Major League team to have nine pitchers reach 1,500 strikeouts. For the second straight season, Cain's ERA hovered in the high 5, finishing with a 5.64 ERA while starting 17 games for the Giants. Cain was left off the Giants 2016 postseason roster.