New York - Marin Cilic, the last remaining Grand Slam winner in his half of the draw, crashed out of the US Open on Friday while Maria Sharapova awaited a controversial return to Arthur Ashe Stadium.
Croatian fifth seed Cilic, the 2014 US Open champion who missed six weeks since Wimbledon with an adductor strain, was eliminated by Argentine 29th seed Diego Schwartzman 4-6, 7-5, 7-5, 6-4.
The South American, now 2-13 against top-10 opponents, plays his first Grand Slam last-16 match against the later winner between French 16th seed Lucas Pouille and Kazak qualifier Mikhail Kukushkin in a draw half without a top-10 player.
Cilic was broken serving for the first set only to break back to win it. Schwartzman failed on his first chance serving for the set in each of the last three sets before making the most of a second chance, denying two break points in a tense final game.
"The last game was terrible," Schwartzman said. "In my mind I can't play. I'm trying to improve my tennis. I'll try to be more quiet in the end of the next match when I finish."
The night feature at the Ashe main court pits five-time Grand Slam champion Maria Sharapova against 139th-ranked US teen wildcard Sofia Kenin.
Sharapova, playing her first Grand Slam since serving a 15-month doping ban, makes her third appearance on the main court, which irks some rivals sent to outer courts.
"Someone who comes back from a drugs sentence - performance-enhancing drugs - and all of a sudden gets to play every single match on Centre Court, I think that's a questionable thing to do," said ousted Danish fifth seed Caroline Wozniacki. "It doesn't set a good example."
Former world number one Sharapova, now ranked 146th, tested positive for the blood booster meldonium at the 2016 Australian Open. She returned from her ban in April and was given a wildcard into the US Open to make her Grand Slam return.
Sharapova, the 2006 US Open winner, has beaten world number two Simona Halep and Hungary's Timea Babos.
Seven-time Grand Slam champion Venus Williams meets Greece's 95th-ranked Maria Sakkari on Ashe as CBS television reports her sister Serena, the 23-time Grand Slam winner who won the Australian Open in January while pregnant, has gone into labour.
US ninth seed Williams, the Open's oldest women at 37, lost to Serena in this year's Melbourne final and to Garbine Muguruza in the Wimbledon final.
Third-seeded Spaniard Muguruza was set to face Slovakian 31st seed Magdalena Rybarikova in a bid to reach the last 16, which would put her ahead in the race for world number one.
A Muguruza victory would oust Halep and Williams from top-spot contention, leaving only current number one Karolina Pliskova and fourth-seeded Elina Svitolina to stop the Spaniard's first trip to the top.
Awaiting Muguruza or Rybarikova will be Czech 13th seed Petra Kvitova, who defeated French 18th seed Caroline Garcia 6-0, 6-4.
Kvitova, the 2011 and 2014 Wimbledon champion, enjoyed Ashe after needing major left hand surgery following a knife attack by a home intruder last December.
"It means a lot," she said. "After everything which I've been through it's happy moments for me."
Italy's Paolo Lorenzi, 35, became the oldest player in the Open Era (since 1967) to reach a Grand Slam last 16 for the first time by defeating countryman Thomas Fabbiano 6-2, 6-4, 6-4.
Also advancing was Spanish 12th seed Pablo Carreno Busta, who ousted French qualifier Nicolas Mahut 6-3, 6-4, 6-3.
The French Open quarter-finalist, who has not dropped a set, seeks a last-eight berth against either Britain's Kyle Edmund or Canadian teen qualifier Denis Shapovalov.
Carreno Busta would become the first player to face four qualifiers at a Grand Slam in the Open Era if Shapovalov wins. And the Canadian would be the youngest player in the US Open fourth round since Michael Chang in 1989.
The most recent qualifier into the Open men's last 16 was Gilles Muller in 2008.