Daniil Medvedev crashed out of the Rotterdam ATP event in the first round on Wednesday, losing in straight sets to Dusan Lajovic and squandering his chance of taking Rafael Nadal's place as world number two, while Andy Murray was beaten by Andrey Rublev in the last 16.
World number three Medvedev was the top seed for this week's tournament following his run to the Australian Open final but was dumped out 7-6 (7/4), 6-4 in just over 90 minutes by Serbian Lajovic, currently ranked 27th.
Russian Medvedev threw his racquet down in anger after being broken in game nine of the second set, having a row with the umpire and starting the final game with a point penalty as a result.
The outburst came towards the end of a tense performance from the 25-year-old which featured eight double faults and 25 unforced errors.
A calm Lajovic served out the 10th game to set up a second-round clash with Borna Coric.
The defeat was painful for Medvedev as he would have replaced Nadal as world number two had he reached the final.
Nadal withdrew from Rotterdam with a back injury.
"I think I was very focused the whole match and not influenced by his good serves and shots," said Lajovic.
"I knew if I stayed in the match, I'd get my opportunities and change the rhythm."
Rublev sees off Murray
Three-time Grand Slam champion Murray was also visibly frustrated during his 7-5, 6-2 loss to Russian fourth seed Rublev.
The former world number one, now ranked 123rd after a series of hip and groin injuries, competed well in the opening set.
But Rublev clinched the crucial break to lead 6-5, before saving two break points as he served it out in the next game.
The second set looked as though it would be another tight affair, but Rublev reeled off five straight games to claim an ultimately comfortable win.
The world number eight will face either David Goffin or Frenchman Jeremy Chardy in the quarter-finals.
Medvedev and Murray join world number seven Alexander Zverev and three-time Grand Slam winner Stan Wawrinka in exiting the tournament early.
Zverev, 23, was dumped out by Kazakhstan's Alexander Bublik on Wednesday in a shock straight sets 7-5, 6-3 defeat.
German Zverev was seeded third in the tournament but was surprised by 43rd-ranked Bublik in just one hour, 19 minutes.
Bublik, who reached the final of last week's tournament in Singapore, will face Tommy Paul in the second round after the American defeated Italy's Lorenzo Sonego 6-4, 7-6 (9/7).
"Beating Sascha is great," Bublik, who has now won his past three matches against top-10 opponents, told atptour.com.
"There were ups and downs for both of us throughout the match, I got a bit lucky and I was perhaps a little more consistent. I'm just enjoying playing matches right now."
Wawrinka was knocked out on Tuesday, losing in straight sets 6-4, 7-5 to Russia's Karen Khachanov.
Former world number four Kei Nishikori, now ranked 45, followed up his win over seventh seed Felix Auger-Aliassime with a 6-3, 2-6, 7-5 victory over Australia's Alex de Minaur to make the quarter-finals.
Sixth-seeded Belgian Goffin, the champion in Montpellier at the weekend, defeated Jan-Lennard Struff of Germany 6-4, 6-0 in his first round tie.
However, Spanish fifth seed Roberto Bautista Agut, the runner-up in Montpellier, was knocked out by Spanish compatriot Alejandro Davidovich Fokina, 6-2, 7-6 (7/3).
Results from the ATP tournament in Rotterdam on Wednesday (x denotes seeding):
Dusan Lajovic (SRB) bt Daniil Medvedev (RUS x1) 7-6 (7/4), 6-4
Alexander Bublik (KAZ) bt Alexander Zverev (GER x3) 7-5, 6-3
Tommy Paul (USA) bt Lorenzo Sonego (ITA) 6-4, 7-6 (9/7)
Alejandro Davidovich Fokina (ESP) bt Roberto Bautista Agut (ESP x5) 6-2, 7-6 (7/3)
David Goffin (BEL x6) bt Jan-Lennard Struff (GER) 6-4, 6-0
Kei Nishikori (JPN) bt Alex De Minaur (AUS) 6-3, 2-6, 7-5
Andrey Rublev (RUS x4) bt Andy Murray (GBR) 7-5, 6-2
Karen Khachanov (RUS) bt Cameron Norrie (GBR) 6-2, 6-2