Vilanova had a tumour removed from his throat in November 2011 before suffering a relapse in December 2012
He stepped down as Barca boss last July to continue his treatment, with Gerardo Martino taking charge.
"FC Barcelona is in immense mourning. Tito Vilanova has died at the age of 45. May he rest in peace," the Spanish club said in a statement released on the club's website.
"The club wishes to express its most heartfelt sympathy to his family, who are being joined in these moments of mourning by FC Barcelona members and fans all around the world, as well as the rest of the footballing and sporting world.
"The Vilanova family has asked for respect for their desire for the strictest intimacy in the moments after his death."
The club added that a "space for condolence" would be opened in the main grandstand at their Nou Camp stadium on Friday.
Rest In Peace Tito, we will all miss you!
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