Even with three receivers already down, the New York Giants were in position to win after Odell Beckham Jr.'s touchdown catch.
Then Beckham was hurt, and suddenly their winless record wasn't the Giants' biggest problem.
Beckham broke his left ankle and Houston's J.J. Watt broke his left leg as two of the NFL's most talented players suffered serious injuries Sunday.
Beckham was carted off the field just a few plays before the Los Angeles Chargers scored the go-ahead touchdown, sending the Giants to a 27-22 loss.
Watt sustained a tibial plateau fracture, leaving the stadium in an ambulance on the way to the hospital. The three-time Defensive Player of the Year had fallen to the ground while being blocked midway through the first quarter against the Kansas City Chiefs.
The Texans also lost linebacker Whitney Mercilus to a chest injury.
Beckham's injury came near the end of a costly day for the Giants' receiving corps.
Sterling Shepard and Brandon Marshall had already departed after spraining their left ankles on the same series in the second quarter, and receiver and returner Dwayne Harris broke a foot in the third quarter.
Then Beckham went down, the Chargers went ahead, and the Giants were so depleted that they had to use tight ends as receivers on their final, futile drive.
"I mean, it significantly altered the game," coach Ben McAdoo said. "We had one receiver left at the end of the ballgame."
They may not have Beckham again this season. The injury could require surgery, and the Giants certainly wouldn't rush back their star in what seems a lost season at 0-5.
He has 25 catches for 302 yards and three touchdowns, including a 48-yard score early in the fourth quarter that may end up being his last one for a while.
He was then hurt after leaping to catch Eli Manning's high pass and Los Angeles cornerback Casey Hayward pinned his ankle making a tackle. Players immediately signaled the sideline and Beckham was eventually carted off in obvious pain with a hand covering his face.
"It was insane," cornerback Eli Apple said. "Did we even have any more receivers? I thought I was going to have to go out and play receiver."
The Raiders also lost four players to injuries, with Marquel Lee (ankle), fullback Jamize Olawale (concussion), linebacker Corey James (knee) and cornerback Antonio Hamilton (knee) leaving their 30-17 defeat against Baltimore. Ravens running back Terrance West departed on the opening drive with a left calf injury following a 13-yard run and did not return.
Green Bay's Jordy Nelson, who scored his sixth touchdown early in the fourth quarter, wasn't on the field during the Packers' final drive. Coach Mike McCarthy said he was being evaluated for an undisclosed injury. They had earlier lost rookie cornerback Kevin King, who had a big hit on Ezekiel Elliott on a screen pass on the first play from scrimmage and later left with a concussion in the first half.
Cowboys rookie cornerback Chidobe Awuzie, who was playing safety as well, left with an injured hamstring for the second time this season. It was his first game back after missing two games by aggravating the injury in Denver.
The 49ers lost cornerbacks Ahkello Witherspoon (concussion) and Asa Jackson (hamstring) at Indianapolis. Colts receiver Krishnan Hogan needed help to get off the field after appearing to hurt his lower left leg on a kickoff return midway through the third quarter and did not return. Linebacker Anthony Walker left in the second half with a hamstring injury.