Seeded only fifth in a tournament he won in 2007 and 2009, Nadal was nevertheless squarely in the spotlight as he played his first hard-court match in 346 days.
After a few tense moments in the opening set, he came through with flying colors, beating 73rd-ranked American Harrison 7-6 (7/3), 6-2 in one hour and 33 minutes.
Nadal was sidelined for seven months recovering from a left knee injury. He returned in February with three clay-court tournaments.
The former World No 1 got his comeback off to a blazing start on clay, with one runner-up finish and two titles.
But he said his knee still wasn’t 100 per cent, and he wasn’t sure if he’d put it to the test on the punishing US hard courts. “I didn’t know if I was going to be able to come here two weeks ago. I’m very happy to be back here,” Nadal said.
With the win, Nadal moved closer to a projected quarter-final match-up with old foe Roger Federer.
u Roger Federer (2) bt Denis Istomin 6-2, 6-3
u Lleyton Hewitt bt John Isner (15) 6-7 (6/8), 6-3, 6-4
u Kevin Anderson bt David Ferrer (4) 3-6, 6-4, 6-3
u Victoria Azarenka (1) bt Daniela Hantuchova 6-4, 6-1
u Caroline Wozniacki (8) bt Alize Cornet 6-4, 3-6, 6-3
u Angelique Kerber (4) bt Irina-Camelia Begu 6-3, 6-2