The third-ranked Djokovic won the Australian Open in January for his first Grand Slam title, then captured the Masters Series event in Indian Wells, Calif., in March.
"This is one of the best tournaments I've won,'' the Serb said in fluent Italian after receiving the winner's trophy from four-time Rome champion Gabriela Sabatini.
Djokovic's third victory of 2008 will move him within 310 points of second-ranked Rafael Nadal in the ATP rankings.
Djokovic acknowledged he is a contender to become No. 1.
"I hope so. But I don't want to think about No. 1 yet,'' he said. "I know a lot of people will start talking now about me being one of the best players. Let's see. I'm taking it as it comes.''
The Rome tournament is an important clay-court warmup for the French Open, which begins in two weeks.
Djokovic improved to 8-1 on clay this season and 25-5 overall. At the Monte Carlo Masters last month, Djokovic withdrew from his semifinal match with top-ranked Roger Federer due to strep throat.
He showed no signs of weakness this week, although many other players did.
Both Djokovic and Wawrinka advanced to the final when their semifinal opponents quit. First, Andy Roddick pulled out with a back problem against Wawrinka, then Radek Stepanek quit with apparent heat stroke against Djokovic.
Djokovic's quarterfinal opponent, Nicolas Almagro, also withdrew with a wrist problem.
Djokovic did not face a seeded player all week, registering wins against Steve Darcis and Igor Andreev in his opening two matches.
Despite the loss, Wawrinka will move to 10th when the new rankings come out Monday. With Federer, it will mark the first time two Swiss players have been in the top 10.
The 22-year-old Wawrinka was the French Open junior champion in 2003.
Djokovic broke Wawrinka's serve in the opening game of the third set when Wawrinka hit a backhand long after a 20-stroke rally.
Trailing 2-3 in the third, Wawrinka called for a trainer and had his lower back treated. He came back and didn't appear to struggle, but Djokovic maintained his lead and broke again to close out the match in little more than 2 hours.
Playing his first Masters Series final, Wawrinka showed some early nerves and double-faulted on his first service point. After settling in, Wawrinka converted his first break point of the match with a forehand passing shot to take a 3-2 lead in the first set.
Wawrinka also displayed a blistering one-handed backhand that Djokovic had trouble dealing with early on.
As the rallies started to last longer in the second set, Wawrinka began to commit unforced errors and Djokovic converted his first break point opportunity of the match to take a 4-2 lead in the second.
"I wanted to stay focused and positive,'' Djokovic said. "The important thing today was doing the right things at the right times.''
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