Last season's silverware winners New York and Sporting Kansas City opened their MLS campaigns with losses on Saturday.
The Red Bulls, winners of the Supporters' Shield for the best regular-season record, were thrashed 4-1 by the Vancouver Whitecaps at the BC Place Stadium.
Scottish striker Kenny Miller scored a brace for the Whitecaps, sending them top of the Western Conference.
In Carl Robinson's first competitive game in charge of Vancouver, they went ahead in the 34th minute after Richard Eckersley blocked a shot in the area with his hand to give away a penalty.
Former Rangers and Celtic striker Miller sent Luis Robles the wrong way with his spot-kick.
Sebastian Fernandez doubled the lead five minutes into the second half, finding the top corner from 25 yards after a counter-attack.
Miller made it 3-0 on 77 minutes by chipping a stranded Robles before substitute Pedro Morales tucked away a Nigel Reo-Coker cutback.
Bradley Wright-Phillips headed in a consolation goal for the visitors in the first minute of additional time.
MLS Cup-winners Sporting Kansas City started their season with a 1-0 loss at the Seattle Sounders.
Substitute Chad Barrett poked in a scrappy 94th-minute winner for the Sounders at the CenturyLink Field.
The Houston Dynamo started their campaign in the Eastern Conference with a 4-0 thrashing of the New England Revolution.
Will Bruin's first-half brace and goals from Oscar Boniek Garcia and Omar Cummings saw the Dynamo to the huge win.
The Columbus Crew are just behind the Dynamo after Federico Higuain netted twice in their 3-0 win at DC United.
FC Dallas held on for a 3-2 win over the Montreal Impact at Toyota Stadium, while Joao Plata's 80th-minute goal saw Real Salt Lake past the Los Angeles Galaxy 1-0.
Gaston Fernandez snatched a point for the Portland Timbers as his 94th-minute header helped them to a 1-1 draw at home to the Philadelphia Union.