With the French Open only two weeks away, Roddick's preparations suffered a new blow when he was beaten 7-6, 4-6, 7-5 by Chile's Olympic champion Nicolas Massu in the first round.
Nadal pulled out of the tournament with a blistered racket hand suffered during his victory at the Rome Masters last week, the 18-year-old's third successive title and one that took his winning streak to 17 matches.
In contrast, top seed Federer beat Spain's Fernando Verdasco 6-4, 6-3 on a chilly Rothenbaum centre court, showing no sign of the foot ligament strain that caused him to miss last week's Rome event.
"I was quite worried going into today's match to be honest," the Swiss told reporters. "I know what a good player he is and what potential he has for the future. But I coped well with it today.
"My feet are good, I don't know if they're one hundred percent yet, that will show after the tough, long matches," added Federer who is hoping to complete his grand slam collection by winning the French Open.
Roddick was philosophical about his defeat and said he remained optimistic for the French Open.
"I'm disappointed but you have to realise you are going to have bad days in this chosen profession," the American world number three
"It's a little disheartening, losing sucks, there's no way round it."
Nadal had been due to play Russian Igor Andreev in the first round on Tuesday but after arriving in Germany he decided to pull out on medical advice, saying the blister he had sustained on his left hand in Rome had turned into a cut that needed time to heal.
"I'm not 100 percent and I only risk worsening the injury in my hand," said the teenager, who remains one of the favourites for the French claycourt grand slam.
Fellow Spaniard Carlos Moya, the seventh seed, also pulled out on Monday saying he was only "70 percent" fit.
BRITISH DUEL
British fifth seed Tim Henman will play compatriot Greg Rusedski in the second round after a comfortable 6-3, 6-4 first- round win over German Lars Burgsmueller.
Rusedski earned his first ATP Tour victory on clay for almost four years by beating German Philipp Petzschner, ranked 304th in the world, 7-6, 3-6, 6-3.
Three-times former French Open champion Gustavo Kuerten of Brazil thrashed Romania's Andrei Pavel 6-2, 6-1 and another former Roland Garros champion, Juan Carlos Ferrero of Spain, beat Austrian Juergen Melzer 6-3, 7-5.
Swedish 11th seed Joachim Johansson lost 6-1, 6-4 to Frenchman Sebastien Grosjean and his compatriot Thomas Johansson was beaten in three sets by Argentina's Juan Ignacio Chela.