Knox faces 28 years in an Italian jail for the 2007 murder of 21-year-old Meredith Kercher in an apartment they shared in the university town of Perugia, after being convicted by a Florence appeals court last year along with her former Italian boyfriend, Raffaele Sollecito.
Sollecito's defense will make its case on Friday, when the case resumes before the Court of Cassation.
Winding up Wednesday's full day of arguments, Knox defense lawyer Carlo Dalla Vedova said the Florence court's conviction of Knox "is not justice, it is a distortion of the facts."
"We are confronted with a very grave judicial error that must be set right," he said before asking the court to overturn the 2014 guilty verdict.
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Knox maintains her innocence. She returned to the United States in 2011 after an earlier appellate court verdict acquitted the pair. She was awaiting the high court's decision in home town of Seattle, and is "worried, very worried," Dalla Vedova said.
The Cassation Court's options include confirming the guilty verdicts, raising the question of extradition for Knox; overturning the convictions and ordering a third appeals trial; or overturning the convictions without a new trial, tantamount to acquittal.
Knox and Sollecito were convicted in 2009 of the murder, then acquitted by a Perugia appeals court in 2011. The Court of Cassation, however, threw out the acquittal in a scathing decision, remanding the case to a Florence appeals court, which convicted the pair.
Now retired, Claudio Pratillo Hellmann, in comments to the Italian news agency ANSA, predicted that the United States wouldn't agree to extradite Knox.
Kercher family lawyer Francesco Maresca said he hoped the Cassation Court would be reach a final decision, confirming the verdicts and ending the long legal saga.