Southampton executive chairman Nicola Cortese has resigned from his post at the club.
The club made the announcement on their official Twitter feed, adding that a search has begun for a new chief executive officer.
Club owner Katharina Liebherr, who in a reshuffle becomes non-executive chairman, said: "With great regret we have accepted the resignation of Mr Cortese.
"He has done a wonderful job and we very much wanted him to stay. A search has now begun for a successor.
"It is business as usual and we will ensure that the manager, team and staff at the club have all the help and support they need."
It is understood Cortese had been contemplating quitting due to divisions between him and Liebherr, who took over as the south-coast outfit's owner after the death of her father Markus Liebherr in 2010.
Cortese became executive chairman in 2009 after being instrumental in the Liebherr purchase of the club earlier that year, and has since overseen Southampton's rise from League One to the Barclays Premier League.
The Italian's departure is sure to cast doubt over the future of Southampton manager Mauricio Pochettino.
There was talk of Cortese considering his position in May, and Pochettino subsequently warned he too would leave Southampton if the executive chairman chose to do so.
Argentinian Pochettino, appointed as successor to Nigel Adkins in January 2013, said last year: "I would not understand staying in this role if Nicola was not here.
"The person that actually called me from the start, told me about the project and put their faith in me was Nicola.
"I have great respect as well for Southampton, the club and the supporters, but Nicola has been the one that has placed his trust and faith in me.
"I wouldn't see myself in this club if it was not for him.
"I think I am a very transparent person, a very honest person.
"We are on the same wavelength about the club and the future of the club so it really would not make any sense if I was at this club and he was not."
Having entered administration just prior to the Liebherr takeover, Southampton began Cortese's first season as executive chairman with a 10-point deduction but soon rose from the bottom of the third tier.
They achieved back-to-back promotions in 2010/11 and 2011/12 as Adkins, brought in as a replacement for Alan Pardew, guided them to the Championship and then Premier League.
After the controversial sacking of Adkins, Pochettino led the Saints to a 14th-placed finish last term, with them ending their comeback top-flight campaign five points clear of the relegation zone.
Southampton are currently ninth in the table and their next match is a league trip to Sunderland on Saturday.