The bottom half of the US Open men's draw, where three-times champion Rafa Nadal resides, has been blown wide open after four of the top-10 seeds crashed out at the first hurdle.
Austria's Dominic Thiem, Greek Stefanos Tsitsipas, Russian Karen Khachanov and Spaniard Roberto Bautista Agut were all sent packing before Nadal restored some semblance of order at Flushing Meadows.
"That's tennis," Nadal, who used a clinical display to beat John Millman in his New York opener, told reporters when asked about the slew of upsets.
Spanish 10th seed Roberto Bautista, who reached the semi-finals at Wimbledon last month, was the first major casualty as he lost 3-6 6-1 6-4 3-6 6-3 to Kazakhstan's Mikhail Kukushkin.
Eighth-seeded Tsitsipas, who reached this year's Australian Open semi-final, was the next out the door as he fell 6-4 6-7(5) 7-6(7) 7-5 to Russian Andrey Rublev during a match in which the Greek lashed out at the umpire saying: "You're French probably. ... You're all weirdos."
Austrian fourth seed Thiem, who was projected to meet Nadal in the semi-finals, then followed his peers to the exits as he suffered a 6-4 3-6 6-3 6-2 loss to unseeded Italian Thomas Fabbiano, making him the highest-seeded casualty.
"I mean, congratulations to him and I'm happy for him. But it was not the real me there on the court," said Thiem, who prior to the tournament downplayed his chances because of a virus he picked up in the build-up to the last major of 2019.
Russian ninth seed Khachanov, who could have faced Nadal in the quarter-finals, was the final victim, falling 4-6 7-5 7-5 4-6 6-3 to Canada's Vasek Pospisil, who recorded his first win this year after missing several months after surgery.
"If you play bad, you can lose," Nadal said. "Tsitsipas had a very tough first round.
"Of course, Karen is a surprise. I think Thiem has been very sick for the last 10 days. I feel very sorry for him.
"Roberto was a surprise. Honestly, I'm very sad for him."
Canadian 18th seed Felix Auger-Aliassime was blasted off the court by countryman Denis Shapovalov while Spain's Pablo Andujar beat 30th-seeded Briton Edmund.
German sixth seed Alexander Zverev avoided joining the list of big-name exits when he outlasted Moldovan Radu Albot 6-1 6-3 3-6 4-6 6-2.
The other seeds to advance to the second round were John Isner, Gael Monfils, Diego Schwartzman, Marin Cilic, Matteo Berrettini, Benoit Paire and Fernando Verdasco.