Residents of the capital described their homes and offices shaking when the first tremor struck at around 10.25am local time (9.25am BST).
The US Geological Survey (USGS) measured the initial quake at magnitude 5.3, placing the epicentre in central Italy at a depth of six miles (10km).
It was followed 50 minutes later by a stronger 5.7 magnitude quake, which caused Rome's metro to be evacuated as a precaution, with some schools calling parents to pick up their children. Just 10 minutes later, a third earthquake measuring magnitude 5.3 hit.
The fourth earthquake struck shortly after 2.30pm local time (1.30pm BST) with a magnitude of 5.2, the USGS said.
Prime Minister Paolo Gentiloni said there was no immediate confirmation of any deaths. “Fortunately, there are no victims so far, but certainly this repetition of strong quakes is alarming for people who have already been so sorely tried," he told a news conference in Berlin.
Their epicentres were recorded at similar depths in Italy's seismically active central region, just miles from Amatrice, the town devastated in August's earthquake, which killed 234 of its residents.
The tower of one of its churches was toppled on Wednesday after surviving the previous disasters.
Much of the region is buried under more than a metre of snow, cutting off electricity and rendering roads impassable, complicating transport and emergency response efforts.
Maurizio Pelosi, the mayor of Capitagno, said that roads in and out of the town were blocked by snow even before the quakes.
A hotel worker in the town near their epicentres, Giuseppe Di Felice, said people could not get out of their homes.“It's apocalyptic,” he added.
The three significant earthquakes were accompanied by more than 70 almost continuous tremors that shook the region, including several over magnitude 4, as recorded by the European-Mediterranean Seismological Centre.
The quakes were also felt in Lazio, Abruzzo and Marche, La Repubblica reported, being followed by four smaller aftershocks.
Small tremors have reportedly been felt in Rome for several weeks but Wednesday's was the biggest seismic event in several months.
It comes after a 6.2 magnitude earthquake killed at least 299 people in the country's central regions in August.
That was followed by at least two more deadly earthquakes in Umbria and Marche in October, both measuring over 6 on the Richter scale.
Reconstruction efforts continue in towns and villages reduced to rubble by the disaster, which forced thousands of people to shelter in emergency camps.
Italy's Apennine mountains lie along an active fault line between the Adriatic and Eurasian plates, causing frequent seismic activity.
Seismologists say previous quakes have stressed the Laga Fault, which is rupturing.
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