Inter Miami rested Lionel Messi and suffered their first defeat since the Argentine joined the club, with a 5-2 hammering at Atlanta United damaging their playoff hopes on Saturday.
Messi had not made the trip to Atlanta, after a busy run of games since making his Miami debut in late July.
Miami coach Gerardo 'Tata' Martino said after the loss that Messi and had been suffering from "muscle fatigue" and that it would have been "very reckless to bring him to play this game".
The 36-year-old had sat out Argentina's World Cup qualifier against Bolivia in La Paz on Tuesday but watched his team-mates from the bench.
Messi was substituted in the final minutes of the 1-0 win over Ecuador on September 7, after scoring the winner, but there have been no reports of an injury.
With no Messi last week, Miami defeated Sporting Kansas City 3-2 but this time it was a very different story for Martino's team.
Miami went ahead in the 25th minute with a superbly taken goal from in-form striker Ecuadorean striker Leonardo Campana .
Dixon Arroyo's shot flew out off the cross-bar and Campana chested the ball down, lost Miles Robinson with a clever touch and then volleyed home with his left foot.
But the response from Atlanta, sixth in the Eastern Conference, was emphatic with three goals in the space of eight minutes.
A glancing header from French midfielder Tristan Muyamba, which struck the inside of the post, was ruled to have crossed the line by the assistant referee.
Five minutes later, Atlanta had the lead when Brazilian winger Xande Silva dribbled to the byline and his pull-back was turned into his own net by Miami defender Kamal Miller.
Miami's defence, without former Spain international left-back Jordi Alba, were reeling and the rampant Atlanta attack took full advantage, Brooks Lennon adding the third in the 44th minute with a sweetly struck shot after being set up by Caleb Wiley.
The blitz of goals left Miami with plenty to ponder at the interval and they came out strongly, pulling a goal back in the 54th minute.
Tomas Aviles' shot struck the arm of Atlanta defender Luis Abram and referee Jair Marrufo pointed to the spot with Campana's composed shot sending Brad Guzan the wrong way.
- No comeback -
Miami have made a habit of second-half comebacks in the club's Messi era but lacking the impact of the former Barcelona star they were unable to build sustained momentum.
As they pushed forward in search of an equalizer, Atlanta caught them on the counter.
The break ended with Georgian substitute Saba Lobjanidze squaring to Greek striker Giorgos Giakoumakis who slotted home his 14th goal of the season, bringing him level with Nashville's Hany Mukhtar joint top scorer in MLS.
Another well-worked swift break resulted in the fifth in the 89th minute with Lobjanidze again the creator, setting up Tyler Wolff to blast home.
Miami remain next to bottom of the Eastern Conference, six points behind D.C United who occupy ninth place, the last playoff spot.
Martino defended the decision to leave Messi and Alba - who he said also had muscle fatigue - at home ahead of a busy run of games with league matches on Wednesday and Sunday before the US Open Cup final on September 27.
"We risked worse consequences if they came to play this game. It has nothing to do with the (artificial) surface," he said.
"Sometimes it is difficult to make decisions because these are also decisive matches but there is a final on the 27th," added the former Argentina national team coach.
Earlier the 'Hudson River derby' between New York City and New York Red Bulls ended goalless.
Later on Saturday, Los Angeles FC host cross-city rivals L.A. Galaxy in their derby while last year's MLS runners-up, the Philadelphia Union host Eastern Conference leaders Cincinnati.