Borna Coric stunned John Isner to reach the Winston-Salem Open quarter-finals, while Roberto Bautista Agut eased through.
Coric inflicted what was the in-form Isner's first ever defeat at the ATP 250 event, claiming a 7-5 6-2 victory in their third-round clash on Wednesday.
The Croatian managed to break the Isner serve three times, the American - winner of titles in Newport and Atlanta recently - bowing out in his home state of North Carolina.
Awaiting Coric in the last eight is Jan-Lennard Struff, who battled past Andreas Seppi 6-3 6-7 (3-7) 7-6 (7-3).
Bautista Agut, the top seed and last year's runner-up, cruised through, beating Marcos Baghdatis 6-3 6-4.
Next up for the Spaniard is Taylor Fritz after the American teenager edged Paolo Lorenzi 7-6 (7-3) 7-6 (7-5).
On the other side of the draw, seeds Steve Johnson and Chung Hyeon progressed.
Johnson, the sixth seed, was too good for Carlos Berlocq 7-6 (7-1) 6-4 and next faces Kyle Edmund after the Brit beat fellow qualifier Marton Fucsovics 6-2 6-1.
Chung led Julien Benneteau 6-4 1-1 when the French 2011 runner-up retired, with Damir Dzumhur awaiting the South Korean after the Bosnian's 7-5 6-3 success against Horacio Zeballos.