It ordered new trials for the 13, who were convicted in relation to the assassination of anti-Mafia Judge Giovanni Falcone in 1992 along with his wife and three bodyguards.
But it also upheld life sentences passed on 21 Mafiosi convicted of being the physical executors of the murder.
Falcone's death in a car bombing, followed two months later by the killing of his colleague Paolo Borsellino, rocked Italy and resulted in tough new anti-Mafia laws.
The court's reasons for overturning the verdicts will be published at a later date, in accordance with normal procedure, but the Italian press is speculating that the court ruled the 13 were physically absent when the murder was decided.
The court's announcement came just days after the 10th anniversary of the murder.
Mr Falcone's sister Maria said: "I am dismayed."
"It seems a sentence that goes against Giovanni's ideas. All the bosses must have been aware the attack was to be carried out."
The 13 had been convicted on the basis of a legal argument at the centre of other major Mafia trials - that decisions on major Mafia murders were made by all top bosses together.
The 21 other Mafia members whose sentences remain in force include the notorious Salvatore "Toto" Riina.
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