Third seed Dominic Thiem failed to take four match points as he was shocked by Diego Schwartzman in the second round of the Rogers Cup in Montreal.
The world number seven had battled back from a set down to lead 5-2 in the decider but lost five games in a row against the Argentinian, who prevailed 6-4 6-7 (7/9) 7-5.
Thiem needed five set points before clinching the second set and failed to take his chances in the decider as he let slip a 5-2 lead.
The Austrian then had three break points to force a tie-break but Schwartzman reeled off five successive points to secure victory in just under three hours.
In the day's other second-round contest, 20-year-old Jared Donaldson had few problems in overcoming Benoit Paire 6-2 7-5.
Donaldson's fellow Americans Sam Querrey and Jack Sock also saw off French opponents, with the former requiring three sets to see off qualifier Vincent Millot while 15th seed Sock needed just two to beat Pierre-Hugues Herbert.
The home crowd had something to celebrate when 18-year-old wild card Denis Shapovalov overcame a difference of 79 places in the world rankings and saved four match points in his 4-6 7-6 (10/8) 6-4 victory against Rogerio Dutra Silva.
Ninth seed David Goffin came from a set down to beat Yuichi Sugita 4-6 6-1 6-4, while 11th seed Pablo Carreno Busta also came through in three sets against Karen Khachanov.
Paolo Lorenzi saw off Frances Tiafoe in three sets but world number 28 Feliciano Lopez was shocked by Hyeon Chung, who clinched a deciding tie-break.
Kevin Anderson, Borna Coric and Ernesto Escobedo also won on Tuesday.