In March, the Court of Cassation overturned Knox's acquittal in the 2007 murder of flatmate Meredith Kercher and ordered a new trial. Today, the high court issued its written reasoning for doing so.
Kercher's body was found in November 2007 in her bedroom of the house she shared with Knox in Perugia, a central Italian town popular with foreign exchange students.
The appellate court noted that the murder weapon was never found, said that DNA tests were faulty and that prosecutors provided no murder motive.
A young man from Ivory Coast, Rudy Guede, was convicted of the slaying in a separate proceeding and is serving a 16-year sentence.
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In the 74-page Cassation ruling, the high court judges said they "had to recognize that he (Guede) was not the sole author" of the crime, Italian news agency LaPresse reported.
They said the new appeal process would serve to "not only demonstrate the presence of the two suspects in the place of the crime, but to possibly outline the subjective position of Guede's accomplices."
It said hypotheses ran from a simple case of forced sex involving Kercher "to a group erotic game that blew up and got out of control."
The high court faulted the Perugia appeals court for "multiple instances of deficiencies, contradictions and illogical" conclusions.
The new court must conduct a full examination of evidence to resolve the ambiguities, it said.
Italian law cannot compel Knox to return for the new trial and her lawyers have said she has no plans to do so.
It is unclear what would happen to Knox if a possible conviction from the new trial is upheld on final appeal. No date for the new trial has been set.
Florence's appeals court was chosen since Perugia only has one appellate court.