World number three Simona Halep was dumped out of the Madrid Open on Tuesday, losing 4-6, 7-5, 7-5 in the last 16 to Belgian Elise Mertens, while Jannik Sinner and Andrey Rublev won their opening men's matches.
Halep, a two-time Grand Slam champion and former world number one, was twice a break up in the final set at 3-1 and 4-3 but finally succumbed after just over two and a half hours of play.
In the men's draw, Italian teenager Sinner booked his place in the second round when his opponent Guido Pella withdrew with a leg injury in the second set while trailing 6-2 4-4.
Pella responded in fiery fashion, opening up a 4-1 lead in the second before feeling discomfort in his right leg which, after receiving medical attention on court, ultimately led to his retirement.
Sinner, the Miami Masters runner-up, will face Alexei Popyrin in the second round after the Australian beat German Jan-Lennard Struff 6-3 7-6 (7/4).
"So it's really important to win this match to have more confidence. I'm happy that I turned it around."
But Canadian pair Felix Auger-Aliassime and Denis Shapovalov both suffered early defeats.
Elise Mertens (BEL x13) bt Simona Halep (ROM x3) 4-6, 7-5, 7-5
Alexander Bublik (KAZ) bt Denis Shapovalov (CAN x11) 6-4, 5-7, 6-4
John Millman (AUS) bt Hubert Hurkacz (POL x12) 5-7, 7-6 (9/7), 6-3
Yoshihito Nishioka (JPN) bt Filip Krajinovic (SRB) 6-2, 6-4
Alejandro Davidovich Fokina (ESP) bt Pierre-Hugues Herbert (FRA) 6-7 (5/7), 7-6 (7/4), 7-6 (7/4)