De Villiers was withdrawn during the second half of his side's 12-6 loss in Cardiff with what appeared a serious problem, and coach Heyneke Meyer revealed his concern after the match.
South Africa await news on injured captain Jean de Villiers
South Africa are anxiously awaiting an update on the knee injury captain Jean de Villiers suffered in Saturday's defeat to Wales.
"Losing our captain was a big setback," said Meyer.
"Jean has had so many knee injuries. I feel really sorry for him and I hope that he will be back for the World Cup."
Those sentiments were echoed by the man who took over as captain following de Villiers' premature exit, Victor Matfield.
And the veteran lock went on to offer a blunt appraisal of the Springboks' November tour, which saw victories over England and Italy bookended by defeats at the hands of Ireland and Wales.
"It's not looking good for Jean," said Matfield.
"He's had a run of bad injuries and we're just hoping that it's not as bad as it looks.
"We're still a year away from the World Cup, but this is not up to our standards and we're not happy with the tour having lost two matches.
"But there are still some senior players to come back and I'm sure we'll come back before the World Cup."
South Africa had winger Cornal Hendricks controversially yellow carded following an aerial collision with Wales full-back Leigh Halfpenny.
"We got the yellow card with 18 minutes to go and the aim was not to concede any points in those ten minutes and we managed that," added Matfield.
"Then we had a chance to score. We didn't get a clean scrum at the end and that cost us. Rugby is a game of centimetres."
There were no excuses from Meyer, after his side were beaten by Wales for only the second time in 30 meetings.
"I thought Wales played well and were the better team," said Meyer.
"We didn't cope well with the pressure and, at this level, you have to convert your pressure.
"You want to win every single game, but there's still time to fix things.
"You have to put guys in a situation and see how they cope. Some of the guys didn't cope, but you have to look at yourself as a coach."
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