In March, the Court of Cassation overturned Knox's acquittal in the 2007 murder of British flatmate Meredith Kercher, 21, and ordered a new trial. On Tuesday, the high court issued its written reasoning for doing so.
The 74-page document picked apart the 2011 appeals court decision that freed Knox, faulting the judges for ignoring some evidence, considering other evidence insufficiently and undervaluing the fact that Knox had initially accused a man of committing the crime who had nothing to do with it.
At one point, the high court said the appeals sentence "openly collides with objective facts of the case."
Among the undervalued pieces of evidence was Knox's own statement to police, written in English after her police interrogation, in which she wrote that while she couldn't remember clearly, she had an image of herself in her apartment kitchen with her hands covering her ears to drown out Kercher's screams.
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. Her throat had been slashed.
Knox, now 25, and her Italian ex-boyfriend, Raffaele Sollecito, 29, were initially convicted of the crime and sentenced to long prison terms.
Both Knox and Sollecito denied any involvement, saying they weren't in the apartment at the time.
A young man from Ivory Coast, Rudy Guede, was convicted of the slaying in a separate proceeding and is serving a 16-year sentence.
In the Cassation ruling, the high court judges sharply criticized the appeals court ruling for not taking into account the sentence against Guede, which said he hadn't acted alone.
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 went out of control."
The high court faulted the Perugia appeals court for "multiple instances of deficiencies, contradictions and illogical" conclusions, saying at one point it used an "absolutely inadequate" evaluation of facts to arrive at an erroneous judgment. The new court must conduct a full examination of evidence to resolve the ambiguities, it said.
Specifically, it faulted the appeals court for undervaluing the fact that Knox had initially identified local bar owner Diya "Patrick" Lumumba as the killer. Lumumba was jailed for two weeks but eventually freed after police determined he had nothing to do with Kercher's murder.
"Even though she was young, Knox was a mature girl with an adequate level of culture, born and raised in a country whose laws don't permit one to gratuitously accuse someone else just to get out of an embarrassing situation," the court said.
It said the failure of the appeals court to consider Knox's false accusation together with the murder charge was "manifestly illogical" and must be reconsidered by the new appeals court.
Knox was convicted of slandering Lumumba; she denies the charge and says she was pressured into making the false accusation by overzealous police interrogators.
The high court judges also sharply criticized the appeals court for glossing over what prosecutors say was a robbery staged by the suspects in the apartment to throw police off their trail.
The judges noted that the glass from a broken window shattered inside the apartment, not outside, indicating that it was broken from the inside. In addition, there was no evidence that the outside wall had been scaled by the purported robber—again indicating it was an inside, staged job, the court reasoned.
Knox left Italy a free woman after her 2011 acquittal, after serving nearly four years of a 26-year prison sentence. Now a University of Washington student in Seattle, she has called the reversal by the Cassation court "painful" but said she was confident she would be exonerated in the new appeals.
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.
In Italy, prosecutors as well as the defense can appeal court decisions.
No date for the new trial has been set. Florence's appeals court was chosen since Perugia only has one appellate court.
Although Knox and Sollecito said they weren't in the apartment that night, they acknowledged they had smoked marijuana and their memories were clouded.
Francesco Maresca, the lawyer for the Kercher family, said Tuesday he was "very satisfied" with the high court decision, saying it had taken into account all the prosecutors' and family's objections to the acquittal.
Knox's attorney, Luciano Ghirga, said the defense would confront the upcoming appeals "serenely ... knowing as always that Amanda and Raffaele weren't in the room of the crime when Meredith was killed," the ANSA news agency reported.
Follow Nicole Winfield at www.twitter.com/nwinfield