Almagro, seeded 11th at the Madrid event, used his clay-court skills to overcome a first-set loss and then rally to beat Colombian qualifier Santiago Giraldo 6-7 (5-7), 6-3, 6-3 at The Magic Box.
The unseeded Ferrero, a former French Open champ, fell 6-4, 7-6 (7-4) to Russian Igor Andreev.
Ferrero took the Madrid title in 2003 when it was an indoor hard-court event.
American wild card Ryan Harrison, Serb Viktor Troicki, Russian Mikhail Youzhny, Spaniards Guillermo Garcia-Lopez and Daniel Gimeno-Traver, and Colombian qualifier Alejandro Falla also logged victories Monday.
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