Youzhny kept Ferrer off balance by using a variety of speed and spin at Ahoy stadium. It was his first win over a top-20 player in a year.
"The magic isn't back yet,'' said Youzhny, who won the event in 2007. "I can do better. Especially when things get tense, I play too cramped.''
Defending champion Michael Llodra defeated Ivo Karlovic 4-6, 6-3, 6-4. Llodra overcame Karlovic's 25 aces with a steady serve and volley game.
Gilles Simon edged Philipp Kohlschreiber 7-5, 7-6 (1). Simon held off two break points in the 10th game of the first set and broke Kohlschreiber in the following game.
Simon will play Mario Ancic, who defeated Rainer Schuettler 7-5, 6-2.
Top-ranked Rafael Nadal will face Simone Bolelli later Wednesday.
Nadal rallies to win at ABN Amro
Nadal rallies to win at ABN Amro
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