Reuben Brigety, the US ambassador to South Africa, said he will resign effective January 10 in line with procedure after Donald Trump's election victory.
Brigety commented in a statement on Monday.
He said this was "in accordance with standard procedure during a change of presidential administration".
Last year, Brigety made headlines when he alleged that weapons were loaded onto a Russian ship between South Africa and Washington.
An investigative panel appointed by President Cyril Ramaphosa found no evidence to substantiate Brigety's claims.
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