Second seed Nadal enjoyed an assured win over spirited wild card Kei Nishikori. The Majorcan, champion in 2008, looked at home as he took to the Wimbledon grass for the first time in two years after missing out with tendinitis 12 months ago.
Faced with 80-degree heat and a talented Japanese opponent, Nadal kept his cool to post a 6-2, 6-4, 6-4 triumph. Next up for the five-time French Open champion is an encounter with Dutchman Robin Haase, who defeated James Blake of the USA 6-2, 6-4, 6-4.
Nadal said: "I'm very happy to come back to this tournament and play in probably the most beautiful and emblematic court in the world."
Eighth seed Fernando Verdasco became the biggest men's casualty so far when he was beaten 7-6 (11/9), 6-2, 6-7 (6/8), 6-4 by Italy's Fabio Fognini.
Robin Soderling barely broke sweat as he booked his place in the second round with a 6-2, 6-2 6-3, victory over Robby Ginepri.
Ninth seed David Ferrer advanced with little drama as he dispatched unseeded German Nicolas Kiefer 6-4 6-2 6-3, while 10th seed Jo-Wilfried Tsonga survived a gruelling four-set battle with American Robert Kendrick, prevailing 7-6 (7/2) 7-6 (8/6) 3-6 6-4.
Mikhail Youzhny, the 13th seed from Russia, 19th seed Nicolas Almagro from Spain and Cypriot Marcos Baghdatis, the No 24 seed, lost to Dudi Sela of Israel, Italy's Andreas Seppi and Slovakia's Lukas Lacko respectively.
Juan Carlos Ferrero, the Spanish 14th seed, became another big-name casualty as he lost a five-set epic to Belgium's Xavier Malisse, 6-2 6-7 (6/8) 7-6 (7/5) 4-6 6-1