Fabrizio Curcio, head of the national civil protection agency, said around a dozen people had been injured but that there did not appear to have been any fatalities.
"We are checking, there are several people injured but for the moment we have had no reports of victims," Curcio said.
The quake struck struck at 7:40 am (0640 GMT) near the small central mountain town of Norcia, unleashing a shock felt in the capital Rome and even in Venice, 300 kilometres (200 miles) away.
It was Italy's biggest quake since a 6.9-magnitude events struck the south of the country in 1980, leaving 3,000 people dead.
Norcia's 14th-century Basilica of Saint Benedict, built on the reputed birthplace of the Catholic saint, was reduced to rubble.
The church is looked after by an international community of Benedictine monks based in a local monastery which attracts some 50,000 pilgrims every year.
"It was like a bomb went off," the town's deputy mayor, Pierluigi Altavilla told Rai News 24.
"We are starting to despair. There are too many quakes now, we can't bear it anymore."
Visibly upset, some of the monks and other residents knelt in prayer before the ruins.
Guiseppe Pezzanesi, mayor of Tolentino in the neighbouring Marche region, said the small town had "suffered our blackest day yet."
"The damage is irreparable. There are thousands of people in the streets, terrified, crying. Let's hope that is an end to it, the people are on their knees psychologically."
Italy's institute of geology and vulcanology (IGNV) measured the quake at 6.5 and said it had been preceded by a 6.1 magnitude shock an hour earlier.
It came four days after quakes of 5.5 and 6.1 magnitude hit the same area and nine weeks after nearly 300 people died in an August 24 quake that devastated the tourist town of Amatrice at the peak of the holiday season.
As with Wednesday's tremors, the impact was mitigated by the fact that any buildings deemed vulnerable to seismic activity had been evacuated.
"Everything collapsed. I can see columns of smoke, it's a disaster, a disaster," Marco Rinaldi, the mayor of Ussita, one of the pretty mountain villages hit hardest by the last quake, told journalists.
"I was sleeping in my car, I saw hell break out," he said.
The quake was powerful enough to set off car alarms in Rome, 120 kilometres (75 miles) from the epicentre, and the capital's underground rail network was closed for structural safety checks.
Much of Italy's land mass and some of its surrounding waters are prone to seismic activity with the highest risk concentrated along its mountainous central spine.
Italy straddles the Eurasian and African tectonic plates, making it vulnerable to seismic activity when they move.
In addition to the Amatrice disaster in August, just over 300 perished when a quake struck near the city of L'Aquila in 2009.
In 1980 tremors near Naples left 3,000 dead and an estimated 95,000 died in the 1908 Messina disaster, when a quake in the waters between mainland Italy and Sicily sent massive waves crashing into both coasts.
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