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.
Former US 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.
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.
No 13 Mikhail Youzhny of Russia crushed Slovak Dominik Hrbaty 6-3, 6-1.
Another former world No 1, 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.
Monday’s results (prefix number denotes seeding):
First round: 10-Tomas Berdych (Czech Republic) beat Benjamin Becker (Germany) 6-3, 6-4; Sam Querrey (US) beat Marc Gicquel (France) 7-5, 5-7, 6-4; 16-David Ferrer (Spain) beat John Isner (US) 7-6 (7-3), 6-3; 11-Ivan Ljubicic (Croatia) beat Amer Delic (US) 1-6, 7-6 (7-3), 6-3; Nicolas Kiefer (Germany) beat Marat Safin (Russia) 6-3, 7-6 (7-1); Fernando Verdasco (Spain) beat Filippo Volandri (Italy) 6-2, 6-2; Carlos Moya (Spain) beat David Nalbandian (Argentina) 7-6 (7-4), 7-6 (7-2); Nicolas Almagro (Spain) beat Florian Mayer (Germany) 7-6 (7-5), 6-4; Jarkko Nieminen (Finland) beat Vince Spadea (US) 6-2, 6-0; Juan Ignacio Chela (Argentina) beat Tim Henman (Britain) 6-4, 3-6, 6-3; Juergen Melzer (Austria) beat Ivo Karlovic (Croatia) 7-6 (7-4), 7-6 (7-2); 13-Mikhail Youzhny (Russia) beat Dominik Hrbaty (Slovakia) 6-3, 6-1.
SAFINA SURVIVES SCARE
TORONTO: Ninth seed Dinara Safina survived a first-round scare at the Toronto Cup on Monday before rallying to tame Frenchwoman Camille Pin 7-6, 3-6, 7-5.
Trailing 4-1 in the third set, Safina swept the next four games to claw her way back before finishing off the 91st-ranked Pin with a forehand winner to end the two hour 36 minute battle.
Safina's victory completed a perfect day for the seeded players with all six in action advancing to the second round.
Patty Schnyder continued her impressive buildup to the US Open with a 6-3, 6-2 win over Spain's Anabel Medina Garrigues.
Twelfth seed Tatiana Golovin of France advanced with a routine 6-2, 6-1 victory over Ukraine's Julia Vakulenko but Israel's Shahar Peer had a tougher passage, the 11th seed battling past Dutchwoman Michaella Krajicek 7-5, 7-6.
Slovenia's Katarina Srebotnik was also made to work for her place in the second round, the 14th seed dropping the first set before roaring back to register a 5-7, 6-2, 6-2 victory.
Czech 16th seed Lucie Safarova also needed three sets to dispose off Uzbekistan's Varvara Lepchenko 6-4, 6-7, 6-1.
Monday’s results:
First round: 9-Dinara Safina (Russia) beat Camille Pin (France) 7-6 (11-9), 3-6, 7-5; 16-Lucie Safarova (Czech Republic) beat Varvara Lepchenko (Uzbekistan) 6-4, 6-7 (2-7), 6-1; Dominika Cibulkova (Slovakia) beat Angelika Bachmann (Germany) 6-2, 6-4; 12-Tatiana Golovin (France) beat Julia Vakulenko (Ukraine) 6-2, 6-1; Yan Zi (China) beat Severine Bremond (France) 6-4, 6-0; Tathiana Garbin (Italy) beat Laura Granville (US) 6-2, 6-0; 14-Katarina Srebotnik (Slovenia) beat Kateryna Bondarenko (Ukraine) 5-7, 6-2, 6-2; 10-Patty Schnyder (Switzerland) beat Anabel Medina Garrigues (Spain) 6-3, 6-2; Flavia Pennetta (Italy) beat Olga Poutchkova (Russia) 6-3, 7-5; Peng Shuai (China) beat Caroline Wozniacki (Denmark) 6-0, 6-7 (4-7), 6-2; Francesca Schiavone (Italy) beat Tamira Paszek (Austria) 6-2, 2-6, 6-3; 11-Shahar Peer (Israel) beat Michaella Krajicek (Netherlands) 7-5, 7-6 (9-7); Roberta Vinci (Italy) beat Nuria Llagostera (Spain) 6-0, 6-0.—Reuters