South Africa coach Carlos Alberto Parreira has quit after 16 months in charge of Bafana Bafana.
The Brazilian and leaders of the country's FA announced his resignation at a news conference on Monday.
Parreira, who will return home to be with his ill wife, said: "My family needs me, especially my wife. After 36 years of marriage, I can't say no."
Joel Santana, currently a coach at Brazilian club Flamengo, is expected to take over from Parreira.
Parreira, 65, had been hired to prepare South Africa for the 2010 World Cup, which the country is hosting.
He put together a young and inexperienced team which suffered a series of poor results and was eliminated in the first round of the African Cup of Nations in Ghana earlier this year.
South Africa slumped to 71st in the Fifa rankings.
But Parreira's tactics seemed to be paying off when South Africa beat Paraguay 3-0 in a friendly last month.
Parreira's resignation takes effect from 2 May.
He will continue as technical advisor, and his two assistant coaches - Jairo Leal and Pitso Mosimane - will remain.
A weekend Johannesburg newspaper report quoted an unnamed SAFA official saying Perreira's wife Leila was battling cancer and not even iconic former president Nelson Mandela could talk the coach out of leaving.
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Parreira guided Brazil to their fourth world title in 1994 and opted to quit a month after being lauded when South Africa gave their finest display for years to outclass Paraguay 3-0 in a Pretoria friendly.
It was the first time in 10 attempts that Bafana Bafana defeated South American opposition since being readmitted to international football in 1992 after three decades of isolation.
South Africa won nine matches, drew six and lost six since Parreira assumed control in February last year.
Bafana Bafana are guaranteed a place at the first World Cup to be staged in Africa as hosts, but must compete in the 2010 qualifiers because they double as elimination matches for the African Nations Cup in Angola the same year.
The first fixture is away to bogey team Nigeria on 31 May followed by Equatorial Guinea (home) and Sierra Leone (away and home) on the following three weekends.
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