South Africa outscored England by seven tries to three to win a Nations Championship first-round match 45-21 at Ellis Park in Johannesburg on Saturday.
After cutting the deficit to 10 points with 11 minutes remaining, England were reduced to 13 men with centre Tommy Freeman and replacement forward Guy Pepper yellow carded.
Prop Thomas du Toit, wings Cheslin Kolbe and Kurt-Lee Arendse, scrum-half Grant Williams, centre Jesse Kriel, hooker Malcolm Marx and loose forward Ben-Jason Dixon scored for South Africa.
Kolbe slotted five of seven conversions for a personal tally of 15 points for the record four-time Rugby World Cup winners.
Prop Ellis Genge and locks George Martin and Alex Coles crossed the tryline for England and fly-half Fin Smith kicked the three conversions.
The wide winning margin gave South Africa a provisional lead in the southern hemisphere table, ahead of arch rivals New Zealand on points difference with both on five points.
The All Blacks edged France 34-32 in Christchurch.
Argentina host Scotland later on Saturday in the final first-round match of the new competition, which pits southern hemisphere teams against those from the north.
Pieter-Steph du Toit deputised as captain of the Springboks after flanker Siya Kolisi withdrew just before the match, along with lock Eben Etzebeth.
"There is a long season ahead and it was a tough game for us. We always knew England would come back, they never stop," said Du Toit, who switched from the back row to lock in a reshuffled pack.
"But we were able to keep to our plan and execute to the perfection that we seek. We never stopped fighting.
"The second half was nice. But we can work on our scrum more. We tried to execute with our tap penalties tonight while seeking more precision."
England also lacked their regular captain with hooker Jamie George taking charge while lock Maro Itoje rests to avoid burn-out.
"I am very proud of the character we showed and the way we fought back, it was a great effort to get so close at the end of the first half.
"When the Springboks put you under that sort of pressure, it is very hard to get out of it, so congratulations to them.
"We pride ourselves on our attack, but we had to spend a lot of time in defence. We did cause their defence some problems. They were able to capitalise and it took us a bit longer to do that."
In a match of three distinct phases, South Africa dominated the first quarter to build a 17-0 lead before a 52,790 crowd on a cold night in the South African financial capital.
England recovered to score twice and close the gap to just three points -- 17-14 -- by half-time as they sought to end a four-match losing streak started in the Six Nations Championship.
The first England try came when South Africa were down to 14 men after Arendse was sin binned for a deliberate knock-on.
After two more tries from the Springboks in the second half, Coles barged over and the Smith conversion left England trailing 31-21 entering the closing stages.
Hopes of a dramatic comeback by the visitors were dashed after Freeman banged his shoulder against the head of South Africa full-back Damian Willemse.
Three minutes later, Pepper joined Freeman in the sin bin for an early tackle.
South Africa took advantage of their numerical superiority with Marx and Dixon scoring and Kolbe, given the goal kicking duties ahead of fly-half Manie Libbok, converting both.
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