Federer, seeking to match Pete Sampras' mark, was at his best on the big points on the opening day when most favorites avoided upsets. However, it wasn't easy for even the top players.
"He is a very tough customer, he played really well," Federer said of the 35th-ranked Seppi. "I think I played well, too. I had to."
Serbia's Ana Ivanovic, the women's runner-up last year, had 10 mistakes in the first five games but managed to advance with a 7-5, 6-3 victory over 107th-ranked Julia Goerges, who was even more erratic.
Top-seeded Jelena Jankovic, short on practice after illness hampered preparations for her pursuit of a first Grand Slam title, had 27 winners to four for No. 104 Yvonne Meusburger in winning 6-1, 6-3.
The other Serbian star, defending men's champion Novak Djokovic, started strong then had to rally from service breaks in the last two sets - he was down 4-0 in the third - to oust Andrea Stoppini 6-2, 6-3, 7-5.
Seventh-seeded Andy Roddick opened with a straight sets win over Bjorn Rehnquist, with fellow American Mary Fish also winning against Samuel Gorth. Six other Americans made first-round exits: Robby Ginepri, John Isner, Robert Kendrick, Bobby Reynolds, Taylor Dent and Sam Querry.
Top-ranked Rafael Nadal has his first match Tuesday, when both Serena and Venus Williams also will be in action.
Second-ranked Federer is a huge fan favorite here, and Rod Laver Arena was still packed when he went on court at 10 p.m. under perfect conditions. Camera flashes went off every time he hit a shot.
"Whose house? Roger's house!" one fan roared.
Federer, who has won three titles here, was clearly focused on proving that fan right.
The Swiss star fended off all 10 of Seppi's break points. He had one stretch in the first set that had the fans gasping and left Seppi with a look that said: "What can I do?"
Federer ran off the last five games of the set, dropping only six points, and the ones that Seppi did win usually took at least two good shots. Twice on one point, Seppi sent up lobs that landed on the line. Federer backtracked to get the first back with a quick flick of the wrist, then got to the second, spun around and whipped a wicked forehand winner.
Things got tighter the rest of the way.
Seppi had a set point as Federer served at 5-6, 30-40 but missed the sideline with a backhand that the replay system showed was maybe a millimeter out. Federer went on to hold, then ran away from a 3-3 tie in the tiebreaker.
Another tiebreaker appeared to be looming in the final set.
Seppi fended off three match points while serving at 5-6. Federer set up another with a backhand volley winner, and Seppi sent a forehand long to end the match in 2 hours, 21 minutes.
Ivanovic lost the 2008 Australian final to Maria Sharapova, who is out with an injured shoulder, then won the French Open to take the top ranking midway through the year.
She had her share of glitches while facing Goerges for the first time, with the midday sun playing havoc with every serve toss at one end of the court. It didn't help that the German player was going for winners.
"I don't expect myself to step on the court and play perfect tennis from very first moment," said Ivanovic, who was ousted in the third round at Wimbledon and in the second at the U.S. Open. "You just want to give yourself the best possible chance and give time to work yourself into the tournament."
Jankovic had more trouble with the broiling daytime sun - temperatures reached 97 degrees - than Meusburger. The surface was so hot that Jankovic iced the soles of her shoes during changeovers.
"My feet were burning," said Jankovic, who didn't know what to expect after her recent illness-enforced layoff.
Roddick was happy to be first up in Rod Laver Arena. He sped off in less than two hours, taking advantage of 31-year-old Swedish qualifier Rehnquist, whose style played right into the Roddick's strengths. Roddick, looking sharp and trim, committed just 10 unforced errors in the 6-0, 6-2, 6-2 win.
Fish had a 6-7 (3), 6-4, 7-5, 6-0 win over local wild-card entry Samuel Groth, but it did not turn out well for other Americans.
Czech Republic's Tomas Berdych, seeded 20th, beat Ginepri, Dominik Hrbaty downed Isner, Kendrick lost to No. 16 Robin Soderling of Sweden, Reynolds was ousted by No. 21 Tommy Robredo of Spain, Dent fell to fellow American Amer Delic in five sets and Querry lost to Philipp Kohlschreiber of Germany.
Other men advancing were No. 8 Juan Martin del Potro and No. 10 David Nalbandian of Argentina, No. 11 David Ferrer of Spain, No. 15 Stanislas Wawrinka of Switzerland, 2005 champion Marat Safin, 2006 finalist Marcos Baghdatis and 16-year-old Australian Bernard Tomic.
Gilles Muller of Luxembourg overcame No. 27 Feliciano Lopez of Spain 6-3, 7-6 (5), 4-6, 4-6, 16-14 in a 4-hour, 23-minute match.
Winners on the women's side included No. 3 Dinara Safina and No. 7 Vera Zvonareva of Russia, No. 15 Alize Cornet of France, No. 16 Marion Bartoli and No. 19 Daniela Hantuchova.
Former fourth-ranked Kimiko Date Krumm, who last reached the main draw of a major since 1996, was beaten 6-4, 4-6, 8-6 by 25th-seeded Kaia Kanepi of Estonia. The 38-year-old Japanese player, who came out of retirement last year, had won three matches in qualifying.
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