Ian Huntley, a 52-year-old former school caretaker convicted in 2003 for the murder of two 10-year-old girls, had been on life support after being hit repeatedly over the head with a metal bar at Frankland prison in northeast England on February 26.
The murders of Holly Wells and Jessica Chapman had transfixed the United Kingdom for two weeks after the best friends vanished from the village of Soham in eastern England on August 4, 2002 after leaving a barbecue to buy sweets.
For 13 days, police searched for the pair, holding out hope they might be alive.
A photo of the girls wearing matching red Manchester United football shirts, taken just before they disappeared, became a fixture of front pages and news broadcasts as detectives mounted a huge hunt.
Thousands visited Soham in an enormous outpouring of concern, leaving hundreds of bouquets outside the local church.
The search ended when a group of hikers discovered the girls' remains beside a dirt path in a wooded area a few miles from the village.
"The murders remain one of the most shocking and devastating cases in our nation's history, and our thoughts are with their families," the UK Ministry of Justice said in a statement.
Huntley denied murdering the two 10-year-olds but was convicted after a trial at London's Central Criminal Court in 2003.
His life sentence recommended he serve at least 40 years.
While in prison, Huntley survived repeated attempts on his life, and he was kept under close protection along with other notorious killers.
In one incident in 2010, his throat was slashed by another inmate.
At the time of the murders, Huntley lived with Maxine Carr, a teaching assistant at Holly and Jessica's school.
Carr gave Huntley a false alibi and was subsequently jailed for 21 months for perverting the course of justice.
She is now living under a new identity.
Huntley and Carr often spoke to reporters during the search for the girls.
Huntley had told them he thought he was one of the last people to see them alive while Carr said she would always keep a card Holly had drawn for her.
UK media have reported that murderer and rapist Anthony Russell, 43, was responsible for the attack that ultimately led to Huntley's death.
Durham Constabulary are investigating the circumstances of the incident that led to Huntley's death and a file is being prepared for the Crown Prosecution Service for consideration for charges.
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