Defending champion Kevin Anderson fell in the second round of the Winston-Salem Open as seeds endured a tough day.
South African fifth seed Anderson, last year's champion in North Carolina, suffered a 7-6 (7-5) 6-4 defeat against Czech Jiri Vesely.
Anderson sent down 16 aces, but he struggled returning and was punished by the 23-year-old.
It was a rough Tuesday for seeds at the ATP 250 event as five in total departed.
Frenchman Gilles Simon went down to Diego Schwartzman 7-6 (7-2) 6-1 and Albert Ramos-Vinolas was beaten by John Millman 4-6 7-5 6-3.
Joao Sousa was well beaten by Lu Yen-hsun 6-2 6-4 and Paolo Lorenzi lost to American wildcard Bjorn Fratangelo 4-6 6-2 6-3.
Spaniards Roberto Bautista-Agut and Fernando Verdasco were among those avoiding upset losses.
Second seed Bautista-Agut was pushed but got past Aljaz Bedene 4-6 6-3 6-3 and 2009 champion Verdasco overcame talented American teenager Taylor Fritz 3-6 6-3 6-2.
Champion in 2014, Lukas Rosol saw his run come to an end in the second round, losing to Steve Johnson 6-3 6-2.
Pablo Cuevas beat Malek Jaziri 7-5 6-1, Pablo Carreno Busta was too good for Jan-Lennard Struff 6-4 7-5 and Sam Querrey edged Guillermo Garcia-Lopez 6-3 6-7 (5-7) 7-5.
Viktor Troicki brushed past Kyle Edmund 6-3 7-5 and Marcos Baghdatis beat Donald Young 6-4 4-6 6-4 despite serving at just 41 per cent.