The club's official Twitter feed tweeted: "The FC Barcelona is in immense mourning. Tito Vilanova has died at the age of 45. May he rest in peace."
Vilanova took over at the Camp Nou ahead of the 2012-13 season having been Pep Guardiola's assistant during the most successful period in the club's history during which they won three out of fourÂ La LigaÂ titles and two Champions Leagues in 2009 and 2011.
Barca went on to make the best-ever start to a La Liga season with 18 wins from 19 gamesÂ but in December 2012 Vilanova was diagnosed with cancer for the second time.
It meant that his assistant Jordi Roura was forced to take charge of the team on occasions when he was undergoing treatment.
At the end of the season Vilanova announced he was resigning to concentrate on his recovery from the illness.
BarÃ§a sent their "deepest condolences" to Vilanova's family and said they would be opening a space in the main grandstand at the Nou Camp for people to express their condolences.
The club's president said on Twitter: "Tito Vilanova was a wonderful person, and will never be forgotten at FC Barcelona. Thank you for everything you taught us. Rest in peace."
JosÃ© Mourinho had several run-ins with Vilanova during his time in charge of Real Madrid, infamously poking him in the eye in one clash.
The Chelsea manager said on the club's Twitter account: "Tito Vilanova's passing is a sad day for football, for Barcelona and most importantly for his family and friends. On behalf of everybody at Chelsea Football Club I send my deepest condolences at this most difficult time."