Vilanova, who has battled a recurring tumor in a saliva gland, was admitted to a local hospital in Barcelona last week. He reportedly had emergency surgery on Thursday.

"It is with sadness that Barcelona must announce that Francesc 'Tito' Vilanova has died today at the age of 45," Barcelona said in a statement on its website. "The death of our former coach occurred this afternoon when he could not overcome this disease which he had battled since 2011."

Several of Barcelona's players paid their respects to Vilanova and offered their condolences to his family.

Lionel Messi posted a photograph of himself with Vilanova on his Facebook page with the message: "We will always remember you. All my sympathy goes to Tito's family."

Goalkeeper Victor Valdes wrote on Twitter that Vilanova was "one of the best managers I have had in my career. Thanks for all that you have given us."

Vilanova first became ill in November 2011, while still an assistant to Guardiola, and took a leave of absence after undergoing surgery. The soft-spoken Vilanova returned and took over from Guardiola the next season, when he led Barcelona to the Spanish league title with a record-tying 100 points.

Vilanova had a second tumor removed in December 2012 and traveled to New York several times during the season to receive further treatment before returning to the sidelines.

In April 2013, Vilanova said he felt fine and "had never thought about quitting." He finished the season before suddenly being forced to resign following a relapse in July.

As an assistant, Vilanova helped Guardiola propel Barcelona into its most successful period and transform a team led by Lionel Messi into the world's best.

With a team that also included several of the players that led Spain to the World Cup title in 2010, Barcelona won 14 of a possible 19 major trophies from 2008-12 under Guardiola before adding the league title with Vilanova in 2013.

Despite the impressive league display, Vilanova was unable to win another Champions League title last season. Barcelona lost to eventual champion Bayern Munich 7-0 on aggregate in the semifinals, one of its most humbling results of the last decade.

As Guardiola's assistant, Vilanova provided the tactical know-how that helped the coach build one of the best teams in the history of the sport — winning two Champions League titles in its impressive haul.

Vilanova will also be remembered for his role in a brawl in the 2010 Spanish Super Cup won by Barcelona, when Real Madrid coach Jose Mourinho poked him in the eye.

Born in the Catalan village of Bellcaire d'Empordà, Vilanova began his career as a player at Barcelona's training academy from 1984-89 but never made it to the first team. Instead, he went on to play for clubs such as Celta Vigo and Mallorca before his career was cut short by a serious knee injury.

Vilanova then went into coaching and got a job in Barcelona's youth system, tutoring current players Gerard Pique, Cesc Fabregas and Messi. Vilanova left to work as sport director at third-division club Terrassa before returning to Barcelona to take over the club's "Barca B" feeder team.

Vilanova is survived by his wife, Montse Chaure, and two children. His son Adrian is currently in Barcelona's youth academy.