Rafael Nadal crashed out of the AMRO World Tennis Tournament on a dismal day for the seeded players in Rotterdam.
The top seed and world number two fell to a surprise 3-6 6-3 6-4 defeat against unseeded Italian Andreas Seppi, who claimed his first win in three meetings with the Spaniard.
Nadal had been the only remaining seeded player in the draw before the second-round match after a bevy of upsets earlier on Thursday.
Second seed Nikolay Davydenko was beaten 6-3 7-5 by Michael Llodra of France, while third-seeded Spaniard David Ferrer suffered a 6-2 7-5 defeat at the hands of German Mischa Zverev.
Czech Tomas Berdych, the number five seed, was also ousted on Thursday in a 6-4 6-4 upset against unseeded Croatian Ivo Karlovic.