South Africa captain Jean de Villiers will see an orthopaedic surgeon in Cape Town this week to gauge the full extent of an injury that could have major World Cup ramifications.
The Springboks centre was carried off midway through the second-half as South Africa slipped to a first defeat against Wales for 15 years at the Millennium Stadium.
Early indications are that the 33-year-old faces a long recovery process after twisting his left knee and suffering a dislocated knee cap.
De Villiers, who has won 106 caps, underwent scans shortly after the match, and Springboks team doctor Craig Roberts said: "The scans revealed significant ligament damage to the inside of his knee and the supporting muscles.
"Jean will return to South Africa and see an orthopaedic specialist in Cape Town early in the week.
"He has had previous surgery on this knee, and the further management of the injury is dependent upon the specialist's recommendations."
South Africa's World Cup campaign kicks off in just under 10 months' time, and there will be major concern in the Springboks camp about the prospects for such an influential player.
Fly-half Pat Lambie added: "Jean is a huge part of this team.
"He is an outstanding leader, he makes great decisions out there, and it is just his presence. Everyone feeds off that.
"It was a huge loss to see him being carried off. We wish him all the very best with his recovery."
South Africa's 12-6 defeat ended an erratic European tour that also saw them beaten by Ireland, but in between, they toppled England at Twickenham and also saw off a resilient Italy side.
"We are very disappointed," Lambie said. "Obviously, it is not the way we wanted to finish off the year and the season. We made some basic mistakes.
"I don't think you can fault the effort or commitment. The boys were really up for this game, and we really wanted to finish off with a positive performance.
"I think we have gained a lot out of this tour. We have learnt some hard lessons, but rather now than in a year's time.
"We will have to go back to the drawing board. Unfortunately, it is a long time before the next Springboks group gets together, but we will come back stronger.
"We were expecting a huge performance from Wales, and that is exactly what we got. It definitely didn't catch us off-guard. We prepared very well, but there were just moments when we let ourselves down."
Springboks coach Heyneke Meyer offered no excuses for his team's demise, which ended a run of 16 successive victories against Wales.
"We always knew it was going to be a very tough Test, especially since we were without a lot of injured players, while some very experienced players were not available because the match fell outside the (autumn) Test window," he said.
"When we lost Jean with more than 20 minutes to go, we had to play with a lot of inexperienced players at the end, especially in the back-line.
"Losing Jean, and the yellow card to Cornal Hendricks shortly thereafter were massive in the context of the game. We were forced to go from an attacking game in the final 20 minutes, where we've been strong in the past, to a defensive mode.
"But we're not going to make any excuses. Wales deserve a lot of credit for their victory. We will take this defeat on the chin, make sure we learn from it and keep our heads up, focused on the task at hand next year.
"We have four Tests left until the Rugby World Cup, and we will have a lot of players back by then who will make a difference."