World Cup-winning forwards Danie Rossouw, Wickus van Heerden and Gurthro Steenkamp withdrew injured on Monday from South Africa's short rugby tour of the UK.
Star scrumhalf Fourie du Preez also looks like staying home and missing the Test against Wales at Cardiff on Nov. 24 and the celebration match with the Barbarians at Twickenham on Dec. 1.
Loose forwards Rossouw and Van Heerden had neck injuries and were replaced by the Blue Bulls' Hilton Lobberts and the Sharks' Ryan Kankowski when the squad assembled yesterday, said planet-rugby.com.
Steenkamp, another starter from South Africa's World Cup final victory last month, cut his hand and had his position filled by Wian du Preez of the Currie Cup champion Cheetahs.
Fourie du Preez, who was married on Saturday, wants to have an operation on the shoulder he hurt in the Super 14, to try and be fully healed before the next Super 14 beginning in February.
Chairman of selectors Peter Jooste said they may not replace Fourie du Preez as they already had two scrumhalves in the squad in Ricky Januarie and Ruan Pienaar.
The latest changes, following last week's withdrawal of fullback Percy Montgomery with a sore knee, mean uncapped Lions prop Heinke van der Merwe was in line to make his Test debut against Wales. Van der Merwe traveled with the second-string Springboks to Australia and New Zealand in the Tri-Nations but didn't play. Kankowski, as the only specialist No. 8 in the touring squad, could also play his first Test.
Meanwhile, captain John Smit will not be released by his new French club, Clermont Auvergne, for the Barbarians game.
Meanwhile, Cardiff Blues prop Gethin Jenkins will become the 125th player to captain Wales when he leads the side against South Africa, the WRU said on Monday.
Jenkins became Wales' most capped prop at the rugby World Cup against Fiji when he overtook Dai Young's tally of 51.
"It's obviously a huge honor, probably the biggest in Welsh sport, but I wanted to be sure I could do justice to the responsibility, my goal as a player is to do everything to the highest of standards and this is no different," said Jenkins, who turns 27 this week.
"Leading the team out at the Millennium Stadium, probably in front of a packed house of home fans and against the world champions will be a pretty special way to win my first cap as captain," he said.
Jenkins takes over the captain's armband from club mate Gareth Thomas.
"Anyone who knows or has worked with Gethin will tell you he sets high standards for himself and those around him," said Wales caretaker coach Nigel Davies, who will pick the team before handing over the job to Warren Gatland on Dec. 1.
New Zealander Gatland was appointed last week to replace Gareth Jenkins, who was sacked after Wales lost to Fiji in their final pool game to miss out on the quarter-finals.
Forwards: Bakkies Botha, Schalk Burger, Bismarck du Plessis, Jannie du Plessis, Wian du Preez, Ryan Kankowski, Hilton Lobberts, Victor Matfield, Johann Muller, John Smit (captain), Juan Smith, Albert van den Berg, CJ van der Linde, Heinke van der Merwe. Backs: Fourie du Preez, Jaque Fourie, Bryan Habana, Conrad Jantjes, Ricky Januarie, Wayne Julies, Akona Ndungane, Wynand Olivier, Ruan Pienaar, JP Pietersen, Andre Pretorius, Francois Steyn.