Top seed Rafael Nadal finished with a clean ace on match point to seal his 300th career victory on clay and advance into the quarter-finals of the Monte Carlo Masters on Thursday.
The eight-time winner here became just the 11th man to crack 300 wins on the dirt: the last to do so was Spaniard Carlos Moya in 2007.
Nadal began his formidable run on the surface with his first clay win in 2002 and has not looked back since. At the top of the all-time table in the victory category is Argentine Guillernmo Vilas, who ended his career standing 644-183 on the surface.
Spaniard Nadal had a few spots of bother against Italy's Seppi, with the world number one forced to save five break points in the sixth game of the opening set for a 5-1 lead.
In the second set, Nadal dropped serve to love while leading 4-2. But he got it straight back for 5-3 and finished off the victory in 93 minutes.
Second seed and holder Novak Djokovic, who beat Nadal for the 2013 title, was facing Spain's Pablo Carreno Busta while fourth seed Roger Federer was to play Czech Lukas Rosol.
Swiss Stanislas Wawrinka earned a free trip into the last eight when Spain's Nicolas Almagro retired before their third-round match with a foot injury.
Australian Open winner Wawrinka, seeded third, will Friday face off against Canadian eighth seed Milos Raonic, who beat 11th-seeded Spaniard Tommy Robredo 6-4, 6-3.
Wawrinka has beaten Raonic in both of their previous meetings, in 2012 and 2013 on hardcourt.
Almagro said he was unable to walk after waking with pain in his foot.
"After consulting with the doctor for a long time this morning, we decided together that it was better for me not to play.
"I deeply regret this because I was expecting a lot from this tournament that I like so much," he said in a statement.
Frenchman Jo-Wilfried Tsonga celebrated his 29th birthday with a win in controversial circumstances over flamboyant Italian Fabio Fognini, as he defeated the volatile 10th seed 5-7, 6-3, 6-0.
"I believe a good part of my career is behind me and I still have a piece of my career left ahead of me," said Tsonga. "I have more maturity and I hope I can use it to my advantage."
Fognini toughed out the opening set but was unable to hang on as he lost the second.
In the third, the Italian was jeered by a public which had largely been in his favour as he appeared not to be trying, winning just four points in the final set and letting loose with a string of expletives in moments of frustration.
"Today I felt a lot better than the first day, where my legs felt very heavy," said Tsonga. "I knew I could stay on the court for a long time.
"In the beginning he was better than I was physically, but I made him play each point and I didn't make any unforced errors."