Xolile Mngeni, 27, who was convicted of shooting Dewani while she was on her honeymoon, had been serving a life sentence for the murder, South Africa's correctional services department has said.
Mngeni had been diagnosed with a rare brain tumour while awaiting trial. The tumour was removed in 2011. He was denied parole on medical grounds in July this year.
He died in the hospital section of Cape Town prison, officials were quoted as saying by BBC.
His death will rule him out as a witness in the trial against Dewani's husband Shrien, the Indian-origin British businessman, which is currently underway at the Western Cape High Court.
Prosecutors alleged that Dewani conspired with Cape Town residents Mngeni, Zola Tongo and Mziwamadoda Qwabe and to kill his wife two weeks after their lavish wedding.
Dewani was extradited from the UK in April and is charged with conspiracy to commit kidnapping, robbery, murder, kidnapping, and defeating the ends of justice and has been receiving treatment at Valkenberg psychiatric hospital his arrival in South Africa.
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