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.
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.
"FC Barcelona is in immense mourning. Tito Vilanova has died at the age of 45. May he rest in peace," said a club statement.
"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.
Barcelona and Argentina forward Lionel Messi paid tribute to his former coach.
"Tito was the 1st person who had faith in me," four-times World Player of the Year Messi said on his Twitter feed. "I was a substitute - then he started me for the Under 16s."
Michel Platini, president of European soccer's ruling body UEFA, also hailed Vilanova's contribution to his old club.
"I was deeply saddened to hear the news of Tito Vilanova's passing," the former France playmaker told UEFA's official website.
"He was a great person and a fantastic coach who will always be remembered for his work at FC Barcelona. I send my condolences to Tito's family and to the club."
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.
Florentino Perez, president of Barca's arch-rivals Real Madrid, also mourned Vilanova's passing.
"I want to express my profound sorrow over the death of Tito Vilanova and pass on, in the name of Real Madrid, our condolences, support and love to his family, FC Barcelona and especially to his wife and children," Perez told the Marca newspaper.
"It is a day of considerable sadness for all fans of football and to recognise his personal and professional life."
Barca sports director Andoni Zubizarreta said the club would offer their support to Vilanova's family.
"A great man has left us, a loving husband, father and a total Barcelona member," said Zubizarreta.
"We have to give our support to the family of Tito. Barca also is his family and we will remember him for ever."
- Sports & Recreation
- Tito Vilanova
- Lionel Messi