James Gandolfini suffered a possible heart attack while on holiday in Rome, said HBO TV network.
The New Jersey-born star had been in Italy to attend the Taormina film festival in Sicily.
James Gandolfini won three Emmy awards for his role as Tony Soprano, a mafia boss juggling his criminal career and family life.
“It is with immense sorrow that we report our client James Gandolfini passed away today while on holiday in Rome, Italy,” said his managers, Mark Armstrong and Nancy Sanders, in a statement on Wednesday night.
“Our hearts are shattered and we will miss him deeply.”
HBO also said the star of The Sopranos, which ran for six series on the cable channel from 1999-2007, would be “deeply missed”.
“He was a special man, a great talent, but more importantly a gentle and loving person who treated everyone no matter their title or position with equal respect,” said its statement.
“He touched so many of us over the years with his humor, his warmth and his humility.”
James Gandolfini was born in 1961 in Westwood, New Jersey, to a school dinner lady and a bricklayer-turned-school caretaker, both of Italian background.
He graduated with a degree in communications from New Jersey’s Rutgers University.
Then he moved to New York, finding work as a bartender and a club manager.
James Gandolfini’s acting career took off in 1992 when he landed a part in a Broadway production of A Streetcar Named Desire.
His breakthrough role came a year later playing a mobster in the movie True Romance.
James Gandolfini’s more recent film credits included In The Loop, Zero Dark Thirty and Killing Them Softly.
He was nominated for a Tony theatre award in 2009 for his role in the Broadway hit God of Carnage.
James Gandolfini is survived by his second wife, Deborah Lin, a former model from Hawaii, whom he married in 2008, and their daughter, Liliana, born last year.
He also leaves a teenage son, Michael, from his first marriage to Marcy Wudarski, his former personal assistant. They wed in 1999 and split three years later.
The Sopranos creator David Chase said James Gandolfini was a “genius”.
“He is one of the greatest actors of this or any time,” he said.
“A great deal of that genius resided in those sad eyes.”
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