The Russian made too many unforced errors and Kiefer, still in the early stages of his comeback after a year out with a wrist injury, took advantage.
"It was just a bad day, that's it," Safin told reporters. "I couldn't put the ball in the court at all. It wasn't really a match.
"I'm not going to kill myself and feel bad for the next month and a half. It happened, but it's not the match that I will remember for the rest of my life, so who cares. Play terribly and that's it. Life moves on."
Former U.S. Open and Australian Open champion Safin, now ranked 24th, started poorly, slipping to 5-0 down and though he got one break back, Kiefer took the set.
The German, ranked 222nd but in the tournament thanks to a protected ranking, broke to lead 2-1 in the second set but Safin gave himself hope when he broke back for 3-3 and held his serve to force a tiebreak.
The Russian then played a woeful tiebreak, double-faulting to hand Kiefer victory, 7-1.
"He's a very tough guy to play against because he puts you under a lot of pressure and he's a very strong person," Kiefer said of the Russian.
"You never know with him, but today I think I played quite good tennis and was very, very smart. I served good, that was the key to the match."
Czech 10th seed Tomas Berdych beat Benjamin Becker of Germany 6-3, 6-4, and 11th seed Ivan Ljubicic of Croatia recovered from a dreadful start to defeat American Amer Delic 1-6, 7-6, 6-3.
Number 13 Mikhail Youzhny of Russia crushed Slovak Dominik Hrbaty 6-3, 6-1.
Another former world number one, Carlos Moya, the 2002 champion, enjoyed a 7-6, 7-6 win over Argentine David Nalbandian to set up a clash with Serb Novak Djokovic, who won the Montreal Masters on Sunday.
Moya came from 3-0 down to win the opening set but the Spaniard let slip a 4-1 lead in the second before recovering to win a second tiebreak 7-2.
Sixteenth seed David Ferrer saw off John Isner, the American who reached the final in Washington eight days ago, 7-6 6-3, and Argentine Juan Ignacio Chela beat Briton Tim Henman 6-4, 3-6, 6-3.
Juergen Melzer of Austria, Spaniards Fernando Verdasco and Nicolas Almagro, Finn Jarkko Nieminen and American Sam Querrey all claimed first-round wins.
