Nel's forensic questioning and ferocious style attracted global interest as the so-called "blade runner" trial was broadcast around the world after double amputee Pistorius shot dead his girlfriend Reeva Steenkamp.
Pistorius claimed he mistook Steenkamp, a model and law graduate, for a burglar when he fired four times through the door of his bedroom toilet in the early hours of Valentine's Day in 2013, a claim that Nel hotly contested.
"You killed a person, that's what you did! You shot and killed her, won't you take responsibility for that?" he said during the trial.
"We can confirm that prosecutor Gerrie Nel handed in his resignation (on) January 30," he said, adding that he would pursue "other interests".
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South African agency News 24 reported that Nel, who was dubbed "the bulldog" during his 25-year career, will be joining Afrikaner lobby group AfriForum to pursue prosecutions on their behalf.
AfriForum refused to confirm or deny the reports but said that there would be an announcement "very soon".
In July, Pistorius was given a six-year jail term after an appeals court upgraded his manslaughter conviction to murder.
Nel led the state's criticism of Pistorius' six-year sentence, calling it "shockingly lenient and disturbingly inappropriate".
Pistorius killed his 35-year-old partner at the peak of his fame, following his historic performance in London in 2012 when he became the first double-amputee to race at Olympic level.
Nel was already well known in South Africa before taking the case but became renowned during the Pistorius trial due to his sharp eye for detail and his take-no-prisoners approach.
His interrogations prompted at least one complaint to South Africa's Human Rights Commission -- which later found Nel had no case to answer.
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