Federer served solidly to make it six matches against the 51st-ranked Seppi without dropping a set.
“It was a bit tougher (than the first round), but I was able to raise my game at a few crucial moments and that was the difference,” said Federer, who rested through October.
“I recuperated and worked a bit to get in shape and can play maybe this (late in the) season in good health, which last year wasn’t the case.”
Fifth-seeded Radek Stepanek of the Czech Republic missed all 16 break points but still beat lucky loser Florent Serra of France 3-6, 7-6 (1), 7-6 (1) to advance.
In the first round, fourth-seeded Marin Cilic beat Philipp Petzschner of Germany 6-4, 6-4 to keep alive his chances of qualifying for the ATP Tour finals in London.
The Croat, a wild-card entry, likely needs to win the Swiss Indoors and do well at the Paris Masters next week to make the eight-player lineup at London. He is currently 12th.
Third-seeded Fernando Gonzalez began play 10th on the list, but the Chilean lost 7-6 (3), 4-6, 6-4 to John Isner of the United States in the late match.
Isner’s victory against the 2005 Basel champion ended a run of three straight first-round exits in the past month.
Another rival for a London place, No. 11 Jo-Wilfried Tsonga, has an injured left wrist and retired from his match on Wednesday at the tournament in Valencia, Spain.
In other first-round action, Stanislas Wawrinka rallied to beat Ivan Ljubicic of Croatia, last week’s winner in Lyon, 6-7 (5), 6-3, 6-4.
The sixth-seeded Swiss was treated for a shoulder injury after the first set. Ljubicic was the last man to beat Federer at his home event, in 2003.
Jeremy Chardy toughed out a 7-6 (4), 6-7 (6), 6-4 victory over seventh seed James Blake from the U.S.
The Frenchman sent down 24 aces and got the only service break of the match to open the third set.
“It was a beautiful victory,” said Chardy, who was on course to meet Federer in the quarterfinals. “I could have won the match earlier, but James is a good player and like all good players he made some good shots at important times.”
Richard Gasquet of France defeated last week’s St. Petersburg runner-up Horacio Zeballos of Argentina 7-6 (3), 6-4.