The first "COVID-tested" flight arrived in Rome from New York on Wednesday, an initiative designed to open up air routes between Europe and the United States blocked by the pandemic.
Despite steps the government has taken to curb the latest outbreak and care for the sick, hundreds of people are still dying daily.
Italy saw a record 993 deaths on Thursday, the highest toll since the outbreak began in the first months of the year.
Alitalia flight from John F. Kennedy airport
Passengers had to show they had returned a negative virus test within 48 hours of getting on the Alitaliaflight from John F. Kennedy airport, and were required to take another test on arrival at Rome's Fiumicino.
Italy is among the countries with the highest numbers of deaths compared to its population with 98 fatalities per 100,000 inhabitants.
Its mortality rate, or the ratio of deaths to infections, stands at 3.47 per cent. Only Britain has a higher rate in Europe with 3.55 per cent.
By comparison, Spain's rate is 2.75 per cent and France is at 2.35 per cent.
100 passengers on board
All 100 passengers on board came up negative, according to the AGI news agency, allowing them to avoid a 14-day quarantine required of other arrivals from the United States.
Italian Health Minister Roberto Speranza warned that "if we drop our guard, we run the risk of finding ourselves in January and February facing a new (infection) surge.
"And that we cannot allow," he told SkyTG24 television.
But the government's colour-coded system of risk rating showed that several regions were deemed to be facing a lower risk, allowing inhabitants to move about more freely.
'Almost a year since we returned to Italy'
Among them was Chiara, an Italian living in the United States who is visiting her parents with her husband and seven-month-old son.
"It's been almost a year since we returned to Italy," she told AFP.
"In April our son was born and so far no one from our family has met him. That's why we are so thrilled."
Wear masks and replace them every four hours
Everyone on board still had to wear masks and replace them every four hours, according to airport authorities.
"This is an extraordinary experiment, because it rekindles hope for air travel, mobility and the economy even in the presence of coronavirus," said Nicola Zingaretti, head of the Lazio region that includes Rome.
On Monday, Abruzzo, the last red region, is also to turn orange, according to regional premier Marco Marilio.
On Thursday, Prime Minister Giuseppe Conte outlined a set of restrictive measures to be put in place around Christmas.
He announced a ban on movements between regions from December 21 until January 6, including for Italians who wanted to spend time in second homes.
Virus-free domestic flights
The move follows the launch in September of so-called virus-free domestic flights between Rome and financial capital Milan. One of the hardest-hit European countries in the pandemic, Italy has recorded more than 60,000 Covid-19 deaths and 1.7 million infections.
Italy's Interior Minister Luciana Lamorgese had tested positive for the novel coronavirus on Monday
Cold and rainy weather in Rome
Cold and rainy weather has spread over Rome and the flu vaccine has been late in arriving this year in Italy.
Experts are concerned a surge in flu cases in January will exacerbate strains on a health care system already struggling to overcome the second wave of coronavirus cases.
Record deaths in Italy
The death toll from Covid-19 has passed the 60,000 mark in Italy, according to an official toll published Sunday.
Restrictive measures aimed at stemming the spread of the virus were nonetheless eased in several regions as the rate of infections stabilised and pressure eased on hospitals.
Italy, the first European country to be hit by the global pandemic, has recorded 60,078 deaths from 1,728,878 infections, the health ministry reported.