Andy Roddick continued his poor start to the clay-court season, beaten 6-3 6-3 by Gilles Simon in the opening round of the Rome Masters.
The 28-year-old former number one also lost to qualifier Flavio Cipolla in the first round of last week's Madrid Open.
Seeded 12 Roddick hit only nine winners compared to the 23 from unseeded Simon on a windy centre court in Rome.
Thre American plays in next week's Nice Open before the year's second Grand Slam, the French Open, from 22 May.
"Nobody likes losing. I'm trying at the moment but the last couple of weeks I haven't felt comfortable," said Roddick.
"Playing some different surfaces is like chalk and cheese. An indoor fast court in Memphis is very different to here but I feel great physically. I feel fine, there's no excuses."
Simon broke Roddick's serve in the first game of the match and quickly recovered a break in the opening game of the second set.
"He moves really well, which you don't want to see when you're short of matches, and on a day like today, where you're not getting clean hits much at all," said Roddick, who committed 27 unforced errors to his opponent's 18.
The American's serve also failed to dominate, with Simon winning the ace count 4-1.
"As soon as we got into rallies it became a battle of not really ball striking but movement. I was coming in second most times," Roddick lamented.
Frenchman Gael Monfils and Japan's Kel Nishikori both withdrew from the tournament before they were due to play on Monday.
Monfils, the 10th seed, was forced to withdraw because of illness, while Nishikori is suffering from kidney stones.
Lucky losers Adrian Mannarino of France and Finn Jarkko Nieminen, who were both beaten in qualifying matches on Sunday, were called up to replace the absent pair.
British number one Andy Murray, who was beaten by Thomaz Bellucci in the third round of last week's Madrid Open, has a bye into the second round.
The world number four faces Xavier Malisse of Belgium after he beat Spaniard Guillermo Garcia-Lopez 7-5 6-2 on the opening day.
"I want to try and win the tournament," Murray said. "I felt last week I did well considering the cirumstances in the build-up to the tournament, I didn't know even on the Saturday night before if I would be playing.
"I got a little bit better every day, I'm feeling better each day, I'm practising well and I've got to try and win my matches now.
"Malisse is a very talented guy, a very good shotmaker, he had a good match with Federer last week so it will be tough."
In other matches, France's Jo-Wilfried Tsonga beat Marcos Baghdatis of Cyprus 6-3 6-2 to set up a match with Roger Federer, while 11th seed Mardy Fish defeated Colombia's Santiago Giraldo 4-6 6-2 6-2 and 15th seed Viktor Troicki eased past Nikolay Davydenko 6-4 7-5.
In women's action, Ekaterina Makarova of Russia beat last year's surprise champion, Maria Jose Martinez Sanchez of Spain, 6-0 5-7 6-4, and Greta Arn of Hungary eliminated former French Open champion and two-time finalist Svetlana Kuznetsova, the 11th seed, 3-6 7-6 (7-4) 7-6 (11-9).
Also, ninth-seed Marion Bartoli of France beat Spanish qualifier Arantxa Parra Santonja 6-2 6-3 and another Spanish qualifier, Anabel Medina Garrigues, eliminated 2005 runner-up Patty Schnyder of Switzerland 6-3 6-2, while 13th seed Ana Ivanovic breezed through when Nadia Petrova retired with Ivanovic leading 6-0 3-0.
The men's and women's tournaments are being played simultaneously at the Foro Italico for the first time in 33 years.
Britain's Jamie Murray and Swiss partner Stanislas Wawrinka lost in the first round of the men's doubles, beaten 6-3 6-4 by Americans John Isner and Sam Querrey.