Nishikori has been sidelined since injuring his groin at the Miami Masters at the end of March, but progressed to round three courtesy of a 6-1 4-6 6-3 triumph at the ATP 500 clay-court event.
The Japanese - who is gunning for his fifth ATP title - needed just under two hours and took seven of the 15 break-point opportunities he engineered.
Next up for the fourth seed is Andrey Golubev. The Kazakh was leading 6-4 5-1 against 16th seed Benoit Paire when the Frenchman was forced to retire.
Fifth seed Tommy Robredo wasted little time in a 6-3 6-4 victory over Australia's Marinko Matosevic.
The Spaniard raced into a 5-0 lead in the opener and made a crucial break at 4-3 to set up victory in the second set.
Ninth seed Ernests Gulbis had suffered first-round defeats in Miami and last week's Monte Carlo Open, but the Latvian returned to winning ways with a 7-5 7-6 (7-1) success over Spanish wildcard Daniel Gimeno-Traver.
Gimeno-Traver pushed hard in both sets and served seven aces, yet Gulbis was able to hold his nerve to come through in one hour and 37 minutes.
Philipp Kohlschreiber will meet Jerzy Janowicz or Jurgen Melzer in round three after the German saw off the challenge of Frenchman Edouard Roger-Vasselin, the 10th seed recording a 7-6 (7-4) 6-2 win.
Elsewhere, Inigo Cervantes came from behind to defeat Dmitry Tursunov 5-7 6-0 6-3, while Dominic Thiem overcame Marcel Granollers 3-6 6-3 6-2.
In round one, Ivan Dodig and Melzer needed three sets to overcome Facundo Arguello and Mikhail Kukushkin respectively, but Martin Klizan and Albert Ramos came through in straight sets against Somdev Devvarman and Nikolay Davydenko.