The world number two, fresh from his victory over top-ranked Roger Federer in the Monte Carlo Masters final where he extended his record run of consecutive wins on clay to 67, has a bye into the second round.
He will meet either Kristof Vliegen of Belgium or veteran Italian Davide Sanguinetti in his opening match.
Should he win the title again this week, the 20-year-old Spaniard would be only the second man after Swede Mats Wilander (1982-1984) to win the tournament in three consecutive years.
With Federer taking the week off, two-times defending French Open champion Nadal is the top seed at the Real Club de Tenis Barcelona.
The field is one of the strongest in recent Barcelona Open memory, including Nikolay Davydenko, Tommy Robredo and David Nalbandian.
Three former world number ones and Barcelona Open champions are playing - Juan Carlos Ferrero, Marat Safin and Carlos Moya - while one of the most in-form players on the tour this year, Argentina's Guillermo Canas, returns after missing the Monte Carlo Masters with a thigh injury.
Should they both advance to the last eight, Nadal and Russian Safin will meet for the first time in their career.
That match-up should havehappened last week in Monte Carlo, only for Safin to throw away a big lead against Vliegen in the round before he was due to face Nadal.
The former U.S. Open and Australian Open champion, whose ranking is hovering outside the top 20, begins against Italian Simone Bollelli, who is outside the top 100.
Safin arrived in Barcelona this weekend ready to make a run at the title he won in 2000.
"I feel like I have my energies back after the disappointment in Monte Carlo," Safin told his official Web site.
"I even thought about skipping Barcelona after my loss in Monte Carlo because I felt completely drained of energies, but the last few days at home have recharged my batteries again.
"Now I'm just trying to be competitive in all my matches and get as many wins under my belt and to hope that my confidence will return, and with that a good streak of wins."
Safin said he had been looking forward to playing Nadal for the first time.
"It (the Vliegen defeat) was one of my most disappointing losses because an easy match turned into a very difficult one, and I was looking forward to playing Nadal who is the king of clay.
"As I have never played him before, I wanted to challenge myself by playing him."
Scotland's Andy Murray was forced to pull out of the event with the back injury that saw him withdraw in Monte Carlo.