
The Swiss top seed, who lost in the third round a year ago at the Foro Italico, ran his record against the big-hitting Croatian who stands 208 centimetres to a perfect 6-0.
The pair have a history of tiebreakers, with nine played over 15 sets; Federer stands 8-1 in deciders won.
"His serve is completely different to any other serve out there because of his size," said the Swiss, twice a Rome finalist. "He's a good net player. Puts a lot of pressure on you.
"He can hit all four corners very easily, it makes it hard to return against him."
The Swiss who is working toward trying to lift the French Open crown that he has never won, will take his next step against Czech Radek Stepanek who booked his place over Luis Horna of Peru 6-4, 1-6, 6-3.
The event is missing three-time champion Rafael Nadal, beaten in the third round by fellow Spaniard Juan Carlos Ferrero and plagued by blisters on his right foot.
"You just have the feeling the draw has opened up tremendously," said Federer, 22-5 this season. "It's an opportunity for everyone, because you favour Rafa against all of those guys.
"It's tough for Rafa. I feel for him. He was on such a great streak for the last three years, but I'm sure he'll bounce back either at Hamburg or Paris anyway," he said of the Spaniard who has lost only two clay matches from his last 105.
"It was difficult to judge the level of my game today," said Federer who had a dozen breakpoint chances against the Karlovic serve and converted twice in the second set.
"You don't play much from the baseline against him. I'm playing well and feeling good, that's the most important thing," said the number one who suffered with glandular fever at the start of the season.
Federer made a comeback to form last month as he won the Estoril event, then lost the Monte Carlo final to Nadal.
Federer lost the first match he played against Stepanek, in Gstaad, six years ago, but has since claimed five straight including a Rome victory in straight sets.
Third seed Novak Djokovic reached his second straight quarter-final in Rome, winning a battle of nearly three hours with Igor Andreev 6-3, 3-6, 6-3.
The victory improved the Serbian's record against the Russian to 4-0 after two wins in 2007 on clay and a Dubai quarter-final this March.
"He's a tough player, especially on clay," said Djokovic, who saved nine of the 11 breakpoints he faced. "That's where he plays his best tennis.
"It was a battle and I'm very happy to have won it."
Djokovic, whose stamina has long been suspect, is playing for the first time since quitting a Monte Carlo semi-final against Federer last month complaining of a sore throat.
His fitness will face a Friday test as he goes against Spaniard Nicolas Almagro, who advanced without lifting a racket after 2007 finalist Fernando Gonzalez withdrew with an adductor injury.
"I have one match more than him, but physically I'll have to recover quickly," said Australian Open winner Djokovic.
American James Blake made more clay progress with a fightback win to oust Spanish specialist Fernando Verdasco 5-7, 7-5, 6-2.