Jan-Lennard Struff shocked fourth seed Marco Cecchinato to advance to the Winston-Salem round of 16, while Nicolas Jarry moved through.
Cecchinato failed to make it past the second round of the ATP 250 tournament, the Italian upstaged by Struff 6-3 6-4 in North Carolina on Monday.
Struff saved both break points he faced while converting two of his own to earn a last-16 showdown with Chilean 14th seed Jarry.
Jarry won his second-round match after topping Italian opponent Andreas Seppi 6-4 6-3.
American Taylor Fritz posted his 14th win of the season with a 6-1 6-4 victory against Malek Jaziri, seventh seed Filip Krajinovic awaiting in the next round.
Steve Johnson - the eighth seed - will play Tommy Paul, who beat Laslo Djere 6-3 7-6 (7-4).
Australian Open quarter-finalist Tennys Sandgren accounted for Ricardas Berankis 6-4 6-3, while 2015 Winston-Salem runner-up Pierre-Hugues Herbert lost 6-2 6-3 to lucky loser Franko Skugor.
Elsewhere, there were wins for Ryan Harrison, Leonardo Mayer, Horacio Zeballos, Taro Daniel, Matteo Berrettini, Guido Andreozzi and Jaume Munar.
Meanwhile, Australian Open semi-finalist and sixth seed Hyeon Chung was leading Guillermo Garcia-Lopez 5-2 in a first-set tie-break when rain suspended proceedings.