Tito Vilanova is stepping down as Barcelona's coach following a recurrence of throat cancer.
Club president Sandro Rosell says Vilanova will 'follow a treatment' that will be 'incompatible' with staying on as coach of the Spanish champions.
Rosell made the announcement on Friday at a hurriedly called news conference.
The 44-year-old Vilanova had twice previously had to take a medical break from his duties at Barcelona, once as Pep Guardiola's assistant in the 2011-12 season and again as their manager last season.
In his single season in charge he led Barcelona to the Spanish league title with a record-tying point 100 points.
Spanish media reported that Joan Francesc Ferrer, known as "Rubi", may be in line to take over.
Ferrer led Girona to the second division playoffs last season and was appointed Vilanova's assistant for the coming campaign to help with technical analysis of Barca's rivals.
Vilanova succeeded his close friend Pep Guardiola at the end of the 2011-12 season after Guardiola - now coach of Bayern Munich - decided to take a year out from football.
The pair, who were at Barca's academy together and coached the B side before stepping up to the first team in 2008, led the club on a spectacular four-year run including two Champions League crowns and three La Liga titles.
Last season, Vilanova helped Barca to a fourth La Liga success in five years.