The highest-ranked American player in the Men's draw is out of the US Open after John Isner lost to Philipp Kohlschreiber in four sets at his home Grand Slam.
The 22nd seed was under pressure in the first when he faced set point at 5-6 down, but Isner hit a forehand into the net to let the German off the hook and his opponent subsequently won the tiebreak.
However, the big-serving 13th seed fought back and, with an early break in the second, held out to level the match at one set each.
In a tense third set, Isner had break point at 5-5, but was helpless to stop a saving forehand winner from Kohlschreiber.
The American then strung together five consecutive unforced errors in the tiebreak to gift the third set to his opponent.
From there, Kohlschreiber was able to resist any push on his own serve from Isner and won the match with another tiebreak to set up a fourth round clash with Novak Djokovic.