The world number 10 lost to Nikoloz Basilashvili after more than two and a half hours on the court.
World number 10 Berdych lost 6-4, 6-7 (5/7), 7-5 to a man ranked almost 100 places below him, after more than two and a half hours on court.
The defeat will hit Berdych's hopes of reaching next month's ATP Finals in London.
The Czech is currently ninth in the race to London, which pits the top eight players of the year against each other.
With world number seven Rafael Nadal injured and already out of the London showpiece, Berdych holds the final qualifying position, although with a slender 220-point lead over Belgium's David Goffin, who is playing in Basel this week.