The brutal stabbing of 21-year-old Meredith Kercher, alleged sex games and multiple trials provided fodder for tabloids on both sides of the Atlantic and inspired books and films.
"I'm still absorbing the present moment, which is full of joy," an emotional Knox, 27, told reporters at a news conference outside her mother's Seattle home on Friday night. "I'm grateful to have my life back."
The Court of Cassation threw out the second guilty verdict against Knox and her Italian former boyfriend Raffaele Sollecito, 31, for the murder, saying there was insufficient evidence to convict either of them.
Kercher, who was born in South London, was found stabbed to death in a house she shared with Knox in the medieval hill town of Perugia in 2007. Rudy Guede, originally from the Ivory Coast, is serving a 16-year sentence for the crime, but judges in the previous trials ruled he did not act alone.
It had been widely expected that, even if the court overturned the previous convictions, it would order a retrial. Instead, both Knox and Sollecito are now definitively cleared.
"Meredith was my friend," Knox said, battling back tears. "She deserved so much in this life. I'm the lucky one."
Knox and Sollecito, who faced some 28 years and 24 years in jail, respectively, have both already served four years in jail after an original conviction in 2009.
The roundabout acquittals almost eight years after the murder are sure to stoke further controversy and questions about the Italian justice system, which has now twice overturned guilty verdicts in the case.
"We shouldn't have had to wait all these years, but we have a good decision today, so we are happy," Knox's Italian defence lawyer Carlo Dalla Vedova said in Rome. He added that when he called Knox in Seattle to tell her the news she was "crying with happiness."
Francesco Maresca, a lawyer for the Kercher family, expressed very different sentiments.
"This is not so much a defeat for the prosecution as a defeat for Italy's justice system," he said outside the courtroom. "The judges said there is a lack of proof and whoever acted with Guede has not been found."
If the conviction against Knox had been upheld, it would probably have sparked a complicated legal bid by Italian authorities to try to have her extradited.
Knox, who returned to Seattle in 2011, and Sollecito have maintained their innocence throughout but Knox's lawyer Luciano Ghirga said before the verdict on Friday that his client was "very, very worried."
Following the 2011 acquittal, the Court of Cassation ordered a new trial. A Florence court convicted them again, saying the murder had been the result of a domestic argument, squashing the previous theory that it happened when a sex game went wrong.
In Friday's verdict, a previous three-year jail sentence given to Knox for falsely accusing Congolese barman Patrick Lumumba of the murder was confirmed. But as Knox has already served four years in prison this has no practical consequences for her.
Cries of jubilation could be heard from Knox's mother's house in Seattle where family had gathered to await the verdict. After the verdict was handed down, people could be seen rushing outside into the backyard with phones pressed to their ears, and later neighbors showed up with food and drinks.
Bill Knox, her grandfather, said by phone he was "relieved and ecstatic" that Knox could finally move on with her life in Seattle, where she has worked as a journalist at a newspaper and is engaged to a rock musician whom she has known since childhood.
"It's been a long time coming. I just want for her to be happy," Bill Knox said. "She is an exciting granddaughter."
