Mutu was sacked by Chelsea in Sept 2004 after testing positive for cocaine.
The Romania international received a seven-month ban from football, but Chelsea took a firm stance on the forward and sacked him before then suing him to recover the money they paid to sign him.
Mutu rebuilt his career first at Juventus and then at Fiorentina once he was able to play again, but the incident has dogged him ever since as Fifa ordered him to pay €17m to Chelsea, and his appeal to the Court of Arbitration for Sport against the fine failed.
He was given a glimmer of hope when the Swiss Federal Court temporarily suspended the fine, but they have now decided the 31-year-old must pay the full amount plus interest.
In a statement they said: "In a ruling on June 10, 2010, the Swiss Federal Court rejected the appeal formed by Adrian Mutu against the decision by the Court of Arbitration for Sport (CAS).
"The CAS ordered the Romanian professional footballer to pay a sum superior to 17million euros to his former employer, Chelsea Football Club Limited (Chelsea)."
The court was keen to highlight that they were unable to make a ruling on the actual decision but rather just the sum involved - €17,173,990 plus interest.
The statement continued: "(The court) first rejected the arguments by which the footballer questioned the impartiality of two of the three arbitrators who rendered the decision.
"On those merits, the federal court recalled that, in the field of international arbitration, it does not retry the case, as a court of appeal would, but can check only certain aspects very limited to the basis of recorded facts in the imposed sentence.
"In this case, the federal court had only to consider whether the amount of damages/interest allocated to the London club violated the core values that all judicial systems should follow.
"They came to the conclusion that this was not the case, so that the Romanian footballer's appeal was unfounded."
It is unclear whether Mutu - who has also been ordered to pay court costs - will be able to pay the full amount after reports in Romania last year suggested the striker was bankrupt.
Chelsea paid Parma €22.5 million (around £15.8m) for Mutu in Aug 2003 and received no money for the striker when he returned to rebuild his career in Italy after serving his ban.
Juventus sold Mutu to Fiorentina for €8 million in July 2006.
The Viola forward is currently serving a nine-month ban after testing positive for sibutramine in January and will be allowed to return to football on Oct 29.
Chelsea have declined to comment.