Philadelphia's impressive NBA home record took a hit when Portland Trail Blazers rolled into town and proved too strong for a 76ers side without Australian Ben Simmons.
Sixers guard Simmons sat out with tightness in his left calf and the hosts were beaten 121-105 by an also undermanned Portland on Thursday night.
"I thought we missed Ben's presence all over the floor," Sixers coach Doc Rivers said.
"He spearheads our defence. We were a bad defensive team tonight, but I thought we were worse offensively."
The 76ers lost at Wells Fargo Center for just the second time in 12 games and the top team in the Eastern Conference dropped to 16-7.
Gary Trent Jr. scored 24 points and Enes Kanter's double-double (17 points, 18 rebounds) led the Blazers (12-9), who were missing Damian Lillard, CJ McCollum and Derrick Jones Jr through injury.
Joel Embiid had 37 points for Philadelphia (31 in the first half on 11-of-17 shooting) and might have topped 40 had he not left the game for about four minutes when he fell awkwardly and tweaked his right knee. He walked straight to the locker room but returned with 90 seconds left in the first quarter.
The 76ers' big man scored 25 points in the second quarter and carried the Sixers as they struggled from outside. They missed all 10 three-point attempts.
Embiid's points tied Andrew Toney's franchise record for most in a single quarter.
In Los Angeles, LeBron James had 27 points, 10 rebounds and 10 assists as the Lakers roared away in the second half for a 114-93 victory over Denver Nuggets.
James moved into third place on the NBA's career field goals list while recording his 96th career triple-double and his second of the season.
His big attacking numbers helped the defending champions to their 17th win in 23 games but James was more impressed by his team's effort on the other end of the court.
"We hang our hats on our defence," James said.
"We're the No.1 defensive team in the league, and we want to continue that."
Jordan Clarkson sank five three-pointers while scoring 23 points and Utah Jazz protected the NBA's best record with a runaway 112-91 road win over Atlanta Hawks.
Boomer Joe Ingles produced six points, four rebounds, four assists and one steal while Bojan Bogdanovic had 21 points and Donovan Mitchell added 18 for Utah (17-5).
Kelly Oubre Jr. scored a career-high 40 points, Stephen Curry had 28 and Golden State Warriors beat Dallas Mavericks 147-116 in Texas.
Luka Doncic led the Mavs with 27 points and Kristaps Porzingis had 25.
In Tennessee, John Wall scored 22 points, Eric Gordon added 20 and Houston Rockets beat Memphis Grizzlies 115-103.
Former Sydney Kings forward Jae'Sean Tate had a season-high 19 points for Houston while rookie Desmond Bane led the Grizzlies with 16.