Novak Djokovic and Andy Murray progressed at the Western & Southern Open, while Dominic Thiem was crushed on Monday.
Djokovic, struggling with neck pain, and Murray moved into the last 16 with contrasting wins at the ATP 1000 tournament.
But the seeds encountered trouble as Thiem was one of six to fall in New York, where the event is being held instead of Cincinnati due to the coronavirus pandemic.
After his win over Alexander Zverev and the upsets, Murray's quarter of the draw has opened up.
DJOKOVIC GETS THE JOB DONE
A day after withdrawing from the doubles due to neck pain, the injury seemed to bother Djokovic again during a 7-6 (7-2) 6-4 victory over qualifier Ricardas Berankis.
The Serbian 17-time grand slam champion required treatment numerous times before closing out a tough victory to improve to 19-0 this year.
Djokovic found himself behind in both sets but Berankis was unable to consolidate any of his three breaks of serve.
Up next for Djokovic is Tennys Sandgren, who upset 15th seed Felix Auger-Aliassime 6-7 (4-7) 6-2 7-6 (7-5).
MARVELLOUS MURRAY EDGES ZVEREV
Murray, playing his first tournament of 2020, overcame Zverev 6-3 3-6 7-5 in a tight battle.
Granted a wildcard to play at the tournament, Murray upset fifth seed Zverev in his first win over a top-10 player since 2017.
Murray also reached the last 16 at an ATP 1000 event for the first time since Madrid in 2017, when he was the world number one.
The Brit, 33, mixed 16 winners with 31 unforced errors, while Zverev had 31 and 49 respectively as he struggled with his serve late in New York.
Murray will face Milos Raonic, who was too good for Dan Evans 6-3 7-5, with no seeds left in their quarter of the draw.
TERRIBLE THIEM AMONG SEEDS TO FALL
Thiem, the second seed, was on court for just 61 minutes as the Austrian was crushed 6-2 6-1 by Filip Krajinovic.
World number three Thiem was able to win just two points against the Krajinovic serve.
Krajinovic will meet Marton Fucsovics after the qualifier upset 14th seed Grigor Dimitrov 7-5 4-6 6-2.
Denis Shapovalov fell to Jan-Lennard Struff for the fourth consecutive time, downed 7-6 (7-4) 3-6 6-4, while Diego Schwartzman also made a second-round exit.
Defending champion and third seed Daniil Medvedev endured no problems in a 6-4 6-4 win over qualifier Marcos Giron, while Karen Khachanov, Roberto Bautista Agut, Matteo Berrettini and John Isner also advanced.