Defending champions Venus Williams and Lleyton Hewitt recorded easy straight-sets victories. Williams demolished Croatian qualifier Mirjana Lucic, 6-0, 6-0, and world No. 1 Hewitt dispatched Nicolas Coutelot of France, 6-2, 6-3, 6-3.
Coming on the heels of the lengthy Safin-Kiefer clash, Williams finished off Lucic in 50 minutes, including a timeout for a trainer to tend to Lucic's blistered feet.
In other women's first-round matches, sixth seed and two-time winner Monica Seles of the United States cruised past Zsofia Gubacsi of Hungary, 6-3, 6-3; No. 7 Kim Clijsters of Belgium thrashed Conchita Martinez Granados of Spain, 6-1, 6-0, in 42 minutes; No. 10 Amelie Mauresmo of France whipped Czech qualifier Iveta Benesova, 6-3, 6-2; and No. 14 Chanda Rubin of the United States lashed countrywoman Jill Craybas, 6-1, 6-3.
The evening session featured third seed Jennifer Capriati taking on fellow American Bethanie Mattek and No. 11 Andy Roddick of the United States battling Dutchman Martin Verkerk.
Both Safin and Kiefer suffered cramping during the four-hour, 31-minute battle, with the 25-year-old German feeling the worst of it. Despite enduring tremendous pain, Kiefer rallied from a break down twice in the fifth set, saving two match points to force a deciding tiebreaker.
In the tiebreaker, Kiefer took a 3-2 lead with a crosscourt backhand winner in the corner before smacking two forehands into the net. After Safin hit a smash to go up 5-3, Kiefer netted a forehand before cramps again sent him down on the court. Safin immediately called for the trainer.
Kiefer managed to get up, with Safin graciously indicating that he should take his time. Kiefer saved a third match point with a service winner but dumped another forehand into the net to end his valiant fight.
Safin has some strong results this season but is still seeking his first title. He reached the final of the Australian Open but was surprised by Thomas Johansson. The mercurial Russian put forth another disappointing effort after reaching the semifinals at the French Open, losing to Juan Carlos Ferrero.
But Safin thrives in the electric atmosphere of the U.S. Open. He advanced to the fourth round in his New York debut in 1998 and captured the crown two years later. Last season, the Moscow native reached the semifinals.
Williams is looking to become the first woman to win three straight titles since Chris Evert reigned from 1975-1978. She enters the final Grand Slam of the year having won three straight hardcourt tournaments.
The 22-year-old American lost her Wimbledon crown when she fell to younger sister Serena in the championship match.
Top-seeded Serena also defeated Venus in the French Open final in June. The two have battled in the title match at three of the last four Grand Slam events.
Another former champion reached the second round as No. 9 Martina Hingis of Switzerland posted a 6-3, 5-7, 6-4 victory over American Marissa Irvin. Hingis is on the comeback trail after missing two months due to ankle surgery.
Ninth seed Carlos Moya of Spain and No. 24 Sjeng Schalken of the Netherlands advanced on the men's side. Schalken was losing to 1998 runner-up Mark Philippoussis, 7-6 (7-1), 6-4, 3-6, 5-3, when the big Australian was forced to retire with a left knee injury.
Last year, Hewitt became the second youngest U.S. Open champion in the Open Era (1968-present) with his rout of Pete Sampras in the final. The fiesty Australian has proved to be a worthy No. 1, tying for the ATP Tour lead with four titles, including his first Wimbledon crown.
Hard-serving Aussie Mark Philippoussis, who was unable to play in the last two of three U.S. Opens because of a knee injury that has seen three surgeries in the past 14 months, was forced to retire in the first round.
He was ahead of Sjeng Schalken of the Netherlands, two sets to one, but had lost the third set and was losing the fourth, 3-5, when his ailing left knee left him in agony. He injured himself in the third set.
Philippoussis, who first injured the knee at Wimbledon in 1999 and had not played in the Open two of the last three years, has undergone three knee surgeries in the past 14 months. He has synthetic cartilage injected into the knee every six months.