Chiliboy Ralepelle and Gurthro Steenkamp are returning to South Africa after being injured in the Springboks' opening tour match against Leicester at Welford Road.
Ralepelle, who captained the side in Friday's shock 22-17 defeat, has to see a specialist over his injured foot - while prop Gurthro Steenkamp has a knee problem.
Tighthead Jannie du Plessis is also doubtful with an injured hand, the South Africa Rugby Union (SARU) confirmed in a statement on their official website.
Prop Wian du Preez and hooker Adriaan Strauss, who both play for the Free State Cheetahs, have been called up as replacements.
Prop Tendai 'Beast' Mtawarira has been cleared to tour with South Africa, after SARU and the sports ministry reached an agreement.
SARU had been alerted to clauses in the National Sport & Recreation Amendment Act 2007, which needed to be completed before Zimbabwean-born Mtawarira's place in the squad could be confirmed.
The act required SARU to provide an explanation to the sports minister for the selection of a non-South African national.
"We are delighted with the news, after discovering this problem during the week," SARU president Oregan Hoskins said on www.sarugby.net.
"The government has been very helpful in expediting the completion of the necessary protocols, and we're all relieved that 'Beast' will be available for selection for the Springboks against France in Toulouse on Friday."