Billionaire Shrien Dewani, 34, was extradited to South Africa from the UK in April after being accused of hiring three South Africans to kill his 28-year-old bride Anni in November 2010.
A series of delays played out over the next four years, including lenghty legal process to extradite Dewani to South Africa and consistent claims by his defence that he was innocent and mentally unfit to stand trial.
Seven members of Anni's family have arrived in Cape Town for the start of the trial.
Before his extradition, Dewani was detained in a hospital in Britain for depression and post-traumatic stress disorder.
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Dewani is charged with conspiracy to commit kidnapping, robbery with aggravating circumstances, murder, kidnapping, and defeating the ends of justice.
Anni died when she was shot in the neck as the couple travelled in a taxi on the outskirts of Cape Town.
Dewani claimed he and his wife were kidnapped at gunpoint as they drove through Gugulethu in Cape Town.
He was released unharmed, but his wife's body was found in the abandoned car the next day.