Second seeded Berdych fell 4-6 7-6(4) 7-6(2) to big-serving Croat Ivo Karlovic while Wawrinka, seeded fourth, suffered a 6-4 6-3 defeat to Frenchman Edouard Roger-Vasselin.
Karlovic, as expected, relied heavily on his booming serve and fired down 23 aces during his victory over Czech Berdych, who wasted a match point in the 10th game of the third set.
Defeat for Berdych means his qualification for the World Tour Finals in London will have to wait; the world number seven would have secured a berth at the O2 had he reached the semi-finals this week in Switzerland.
Wawrinka, currently eighth in the standings, also slipped up in his bid to reach London and his lead over ninth-placed Richard Gasquet is just 30 points with the Frenchman still to open his campaign in Basel on Wednesday.
Defending champion Juan Martin Del Potro plays his first match of the week against Henri Laaksonen on Wednesday, while Roger Federer is in second-round action against Denis Istomin.
Swiss Indoors results
Ivo Karlovic (Croatia) beat 2-Tomas Berdych (Czech Republic) 4-6 7-6(4) 7-6(2)
Edouard Roger-Vasselin (France) beat 4-Stanislas Wawrinka (Switzerland) 6-4 6-3
6-Kei Nishikori (Japan) beat Marco Chiudinelli (Switzerland) 6-2 6-4
Daniel Brands (Germany) beat 7-Andreas Seppi (Italy) 7-6(3) 6-3
Denis Istomin (Uzbekistan) beat Horacio Zeballos (Argentina) 7-5 7-6(3)
Marcos Baghdatis (Cyprus) beat Benjamin Becker (Germany) 7-6(8) 6-1
Ivan Dodig (Croatia) beat Carlos Berlocq (Argentina) 2-0 (Berlocq retired)