The bonds were found hidden in false compartments in three safety deposit boxes transferred in 2007 from Hong Kong to Zurich and eight arrests have also been made in Italy as part of the investigation, prosecutors said.
Investigators said that members of a criminal network had tried to use the bonds in emerging markets or give them to banks in exchange for money.
The bonds were dated 1934 and one of the deposit boxes also contained a forgery of the Treaty of Versailles, which investigators said could have been used to justify the sums involved as payments between states following World War I.
The operation was "the biggest for this type of investigation," Giovanni Colangelo, the head of the prosecutor's office in the city of Potenza in southern Italy which is leading the investigation, told reporters.
"Everything began with an investigation into mafia clans in the Vulture-Melfese area" in the southern Basilicata region, Colangelo said.
The investigation has allowed detectives to uncover "an international network with people implicated in numerous countries," he said, adding that he believed that more fake bonds were still hidden.
Contacted by AFP, the US embassy in Rome declined to comment.
Prosecutors said experts from the US Federal Reserve and the embassy had examined the fake bonds and found they were high quality.
"The counterfeiting of bonds, the transfer of the deposit boxes from Hong Kong to Switzerland, the global travel (of the suspects) had an enormous cost and we think that the interests are at a high level," Colangelo said.
Friday's was by no means the first seizure of fake US bonds by Italian authorities but by far the one with the highest face value.
In September 2009, Italian police seized $116 billion in phoney bonds and arrested two Filipino nationals carrying them at Milan's airport.
In June of the same year police arrested two Japanese nationals on the Italian-Swiss border carrying bonds with a face value of $134 billion.