He took over at the Nou Camp ahead of the 2012-13 season having been Pep Guardiola's assistant during the most successful period in Barca's history in which they won three out of four La Liga titles and two Champions Leagues in 2009 and 2011. (Agencies)
Barcelona went on to make the best-ever start to a La Liga season with 18 wins from 19 games but, in December 2012, Vilanova was diagnosed with cancer for the second time.
It meant his assistant Jordi Roura had to take charge of the team on those 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.
"Tito Vilanova has passed away today at the age of 45. It happened this afternoon as our former coach was not able to overcome a disease he has fought since 2011," said Barcelona.
"The club wishes to express their deepest condolences to his family with whom it shares their pain in these moments as do fans, members of FC Barcelona and all the world of football and sport," added a club statement.
Jose Mourinho, a former Barcelona assistant coach, was quoted in a tweet from his current club Chelsea saying: "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."
Juventus coach Antonio Conte added: "I'm saddened by the death of Tito Vilanova, who was a great fighter in life and on the pitch. We will miss him."
Vilanova, a midfielder came through Barca's youth system but was let go in 1990, played for several lower league teams before finally getting his chance in the Spanish top flight with Celta Vigo where he played for three season in the mid-1990s.
It was as a coach though that he made his mark and he began working with the Barcelona youth teams, training future first team players like Lionel Messi, Gerard Pique and Cesc Fabregas.
After several seasons away from the Catalan club he returned in 2007 as assistant to Guardiola with the Barca B team. The following season the pair took charge of the first team and Vilanova went on to play a key role in the club's success.
He took over at the Nou Camp ahead of the 2012-13 season having been Pep Guardiola's assistant during the most successful period in Barca's history in which they won three out of four La Liga titles and two Champions Leagues in 2009 and 2011.