South Africa centre Jean de Villiers and forward Willem Alberts missed the squad’s final training session before their tour of Europe through injury on Wednesday.
The world champions face the prospect of playing Ireland in Dublin on Saturday without any match-fit midfielders.
“We have had our challenges with the number of injuries, particularly among the centres, but that’s not unusual in international rugby,” coach Peter de Villiers said in a statement.
“The players have shown a great attitude in training and we now have to take that on to the field. Ireland have a good record against us in Dublin in recent years.”
The Springboks have lost flank Schalk Burger, centre Juan de Jongh and scrumhalf Ricky Januarie since the squad was announced on Saturday. They have been replaced by fullback Zane Kirchner, veteran centre Adrian Jacobs and uncapped flank Deon Stegmann.
France-based utility back Frans Steyn has been ruled out of the Ireland match after his club Racing Metro refused to release the World Cup-winning centre for a match that falls outside the International Rugby Board’s official Test window.
The touring party arrives in London on Thursday morning on two separate overnight flights from Johannesburg before transferring to Dublin.
The Springboks also play Wales, Scotland and England on the tour as they seek to become the first South African team since 1960 to beat all four home unions.