The Frenchman joined Liverpool as a director of football strategy in November 2010, with his role redefined in March last year.
During that time he has overseen a number of high-profile signings, including the club-record £35million acquisition of Andy Carroll from Newcastle, while he also survived a change of manager when Kenny Dalglish returned to the club to replace Roy Hodgson.
A club statement from principal owner John Henry read: "We are grateful for all of Damien's efforts on behalf of Liverpool and wish him all the best for the future."
Chairman Tom Werner added: "The club needs to move forward and we now have a huge game on Saturday. It is important that everyone joins us in supporting the manager and gets behind Kenny and the team and focuses on a strong finish to the season."
Comolli himself, who has also worked for Arsenal and Tottenham, said: "I am grateful to have been given the opportunity to work at Liverpool and am happy to move on from the club and back to France for family reasons. I wish the club all the best for the future."
Dalglish said: "I had a fantastic working and personal relationship with Damien since he came here. It is disappointing but I suppose there is not much in football which comes as a surprise."
As well as playing a part in the signing of Carroll, Comolli also contributed to one of the most dramatic days in the history of the Premier League by helping along the deal that took Fernando Torres to Chelsea for ?50million late on the same day.
Other signings to have headed to Anfield while Comolli has been in office include the likes of Luis Suarez, Jordan Henderson, Charlie Adam, Stewart Downing and Jose Enrique who, between them, purchased for a total touching £90million.
They have not all been universally popular additions to the Liverpool squad, though, with some fans questioning the merits of paying such high prices for players who have yet to make a consistent impact at Anfield.
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Source: PA