Spaniard Ferrer was the headline casualty of the second round as he made an early exit once again, at the hands of Russia's Teymuraz Gabashvili.
The four-time runner-up was beaten in the first round last year, and he was no match for Gabashvili at the ATP 500 clay-court event, losing 6-4 6-2.
Ferrer started both sets badly by losing his opening service game, and he struggled to contain Gabashvili from there.
The world number five was unable to handle the powerful groundstrokes of his opponent, with Gabashvili showing excellent movement around the court to stay in the rallies.
The Russian eventually completed victory in 82 minutes to book his place in round three.
Eight-time champion and top seed Nadal was also given a scare in his match with compatriot Albert Ramos, but he eventually came through 7-6 (7-2) 6-4.
The opening set saw Ramos break first but Nadal did not allow him to consolidate as he levelled immediately, before the set went to a tie-break.
Nadal dominated in the shoot-out and secured the advantage, before surviving break-point opportunities in his first service game of the second set and going on to convert his own chances in the 10th game to close out victory.
Ivan Dodig will meet Nadal next after the Croat beat 13th seed Feliciano Lopez 6-1 6-4, while seventh-ranked Jerzy Janowicz fell 6-4 7-6 (7-1) against Jurgen Melzer.
Italian Fabio Fognini, seeded third, was 6-0 4-0 down after just 38 minutes against Santiago Giraldo when he was forced to retire with a thigh injury.
And eighth seed Alexandr Dolgopolov will also play no further part in the tournament after home hope Albert Montanes edged him 7-6 (7-5) 6-3.
Nicolas Almagro had no such problems as he booked a third-round spot with a 7-5 7-6 (7-4) win over Martin Klizan.
Meanwhile, there were wins for 11th seed Fernando Verdasco, 6-4 6-3 over Kenny De Schepper, and 12th-rated Marin Cilic, who beat Andrey Kuznetsov 6-1 7-6 (7-2).