Cameron Norrie fell at the first hurdle at the US Men's Clay Court Championship after world number 372 Janko Tipsarevic beat the British number two 6-3 6-4.
The 23-year-old was seeded third at the tournament in Houston, but was immediately on the back foot after the Serbian, ranked more than 300 places lower, broke in the first game.
Norrie went on to lose three more breaks as Tipsarevic sealed the first set in a little more than 30 minutes and won the tie on his second match point.
Reigning champion Steve Johnson also fell 6-3 6-3 to Daniel Elahi Galan Riveros, while two-time runner up Sam Querrey beat Guillermo Garcia-Lopez 6-4 6-3 and Jordan Thompson overcame Santiago Giraldo 4-6 7-6 (1) 7-5.
At the Grand Prix Hassan II in Marrakech, top seed and world number three Alex Zverev lost in a three-set showdown with Jaume Munar 7-6 (1) 2-6 6-3 and will play Benoit Paire, who saw off eighth seed Pierre-Hugues Herbert 6-4 6-2.
Elsewhere, Philipp Kohlschreiber lost to Pablo Andujar-Alba 7-6 (6) 6-4 and Jiri Vesely beat Juan Londero 6-3 6-4.