European Parliament President David Sassoli died overnight, his spokesperson said early on Tuesday.
The Florence-born journalist-turned-politician was 65.
"I am deeply saddened by the terrible loss of a great European & proud Italian," said European Commission President Ursula von der Leyen via Twitter.
"David Sassoli was a compassionate journalist, an outstanding President of the European Parliament and, first & foremost, a dear friend.
"My thoughts are with his family.
"Riposa in pace, caro David! "Rest in peace David, my dear friend".
Sassoli died at an oncological centre in Aviano, in the northeastern province of Pordenone, after being hospitalized on December 26 with serious complications related to an immune-system dysfunction.
President Sergio Mattarella said that he was "deeply pained" by the "unexpected and premature" death of Sassoli.
"His death opens a vacuum in the ranks of those who believed in and built a Europe of peace at the service of the citizens and it is a source of profound pain for the Italian people and the European people," the head of State said.
"His limpid, constant, passionate commitment contributed to making the Strasbourg assembly a lead player in the political debate in a highly delicate period, giving voice to the hopes of the European citizens".
Italian Premier Mario Draghi hailed Sassoli as a "man of the institutions, a profound European, a passionate journalist".
"Sassoli was a symbol of balance, humanity, generosity," Draghi said.
"These qualities were always recognized by all his colleagues, of all political persuasions and of every EU country, which bears witness to his extraordinary civil passion, capacity to listen, (and) constant commitment at the service of citizens.
"His premature and sudden passing dismays us".
European Council President Charles Michel described Sassoli as a "sincere, passionate European".
"We already miss his human warmth, his generosity, his cordiality and his smile," Michel said.
A political science graduate from Rome University, Sassoli worked for several newspapers before joining RAI in 1992.
He worked his way up the State broadcaster and became a news reader for its flagship TG1 news show.
He entered the political fray in 2009, getting elected as an MEP for the centre-left Democratic Party (PD).
He was elected president of the European Parliament in 2019.
Last month he announced he would not stand to be re-elected in that role.
He had been seriously ill with pneumonia in September.
Flags were hung at half mask at the European institutions on Tuesday as a sign of mourning.
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