World Cup winners Faf de Klerk and Cheslin Kolbe will both miss South Africa's autumn Tests in Britain because of injury.
De Klerk has been sidelined due to a hip issue and Kolbe has a knee problem.
Some reports suggest that De Klerk could be out of action for five months.
Springboks lock Pieter-Steph du Toit was also not considered as he continues his recovery from a shoulder injury.
Springboks head coach Jacques Nienaber says it’s always unfortunate to lose players due to injury but they have a good depth of players in their squad and these are established players who have proven themselves at the highest level.
South Africa face Wales in Cardiff on the 6th of November, before playing Scotland seven days later, followed by England at Twickenham on the 20th of November.
Meanwhile, Springboks fly-half Morne Steyn has announced his retirement from international rugby.
The 37-year-old Bulls player made his Test debut in 2009 and went on to win 68 caps and score 742 points.
Steyn is best known for twice kicking series-winning penalties against the British & Irish Lions, in 2009 and this year.
South Africa squad
Forwards: Thomas du Toit, Steven Kitshoff, Vincent Koch, Ox Nche, Trevor Nyakane, Joseph Dweba, Malcolm Marx, Bongi Mbonambi, Lood de Jager, Eben Etzebeth, Salmaan Moerat, Marvin Orie, Siya Kolisi, Kwagga Smith, Marco van Staden, Duane Vermeulen, Jasper Wiese, Franco Mostert.
Backs: Herschel Jantjies, Cobus Reinach, Grant Williams, Elton Jantjies, Handre Pollard, Lukhanyo Am, Damian de Allende, Jesse Kriel, Aphelele Fassi, Willie le Roux, Makazole Mapimpi, Sbu Nkosi, Damian Willemse, Frans Steyn
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