The United States crashed to their first ever World Cup qualifying defeat against Panama on Sunday as coach Gregg Berhalter's decision to ring the changes backfired.
Anibal Godoy's glancing header on 54 minutes secured all three points for Panama at Panama City's Rommel Fernandez Gutierrez Stadium to jolt the USA's bid to reach next year's finals in Qatar.
It was a deserved win for Panama, who created the better scoring chances against a disjointed USA line-up.
The US had moved to the top of the CONCACAF qualifying standings after a 4-1 win over Honduras last month was followed by a 2-0 win over Jamaica in Austin last Thursday.
But the momentum built up by those two wins evaporated after Berhalter named a new-look starting line-up for Sunday's clash against Panama, who qualified for the 2018 World Cup finals at the USA's expense.
Only four players who started Thursday's win over Jamaica were named in Sunday's starting line-up, with forwards Brenden Aaronson and goalscoring teenager Ricardo Pepi both left on the bench.
In their absence, the US struggled to offer any kind of attacking threat against a Panama team who could have taken the lead early on when Rolando Blackburn just failed to tap in a cross from Freddy Gondola.
Gondola then squandered a golden chance to open the scoring on 34 minutes, breaking clean through on goal from Alberto Quintero's pass only for US goalkeeper Matt Turner to produce a fine one-handed save.
Turner saved the US again on the stroke of half-time tipping over a fierce shot from Edgar Barcenas.
Berhalter made changes at half-time with Tyler Adams replacing Yunus Musah and Aaronson coming on for Paul Arriola.
But the changes could not prevent Panama from taking the lead on 54 minutes, when Eric Davis's corner into the area was met by Godoy.
US striker Gyasi Zardes appeared to get the final touch but the goal was credited to Godoy.
Panama moved up into third place in the CONCACAF standings with the victory, level on eight points with the USA, who are second.
In other games on Sunday, Mexico regained first place in the standings after goals from Francisco Cordova, Rogelio Funes Mori and Chucky Lozano were enough for a 3-0 win over 10-man Honduras in Mexico City.
Honduras's veteran defender Maynor Figueroa was sent off for the visitors early in the second half for a brutal challenge on Raul Jimenez.
Mexico now lead the eight-team final qualifying round with 11 points from five games, three clear of the United States.
In other games on Sunday, Canada were frustrated with a 0-0 draw against Jamaica in Kingston while in San Jose, Costa Rica came from behind to beat El Salvador 2-1.
Jairo Henriquez put El Salvador 1-0 up in the 12th minute, before Bryan Ruiz and Celso Borges scored two goals in six minutes to give 'Los Ticos' a boost ahead of their game against the USA in Columbus on Wednesday.