Toronto FC's CONCACAF Champions League hopes were left in tatters following their 4-0 first-leg demolition at the hands of Independiente in the last 16.
Last year's finalists Toronto missed a penalty and conceded three goals in the second half as the MLS team were left with a mountain to climb on Tuesday.
Toronto were playing their first competitive match since selling star attacker Sebastian Giovinco to Saudi Arabian giants Al-Hilal last month - United States international Jozy Altidore's future is also uncertain.
And Toronto were put the sword by Panamanian hosts Independiente, who opened the scoring via Abdiel Ayarza in the ninth minute.
Toronto debutant Terrence Boyd, who arrived from Darmstadt in Germany, had the chance to equalise before half-time but he sent his penalty over the crossbar.
Independiente punished the visitors after the break, with Omar Browne and Romeesh Ivey's brace putting Toronto on the verge of elimination.
Fellow MLS side Houston Dynamo, however, were far more successful after edging Guatemalan hosts Guastatoya 1-0 in the opening leg.
Veteran captain DaMarcus Beasley's strike gave Houston a priceless away goal and dream start in the round of 16.
Meanwhile, Deportivo Saprissa defeated Tigres UANL 1-0.