World Cup winners Faf de Klerk and Cheslin Kolbe will both miss South Africa's autumn Tests in Britain because of injury.
Sale Sharks scrum-half De Klerk has been sidelined by a hip issue and winger Kolbe has a knee problem.
Some reports suggest De Klerk could be out of action for five months.
Current world player of the year Pieter-Steph du Toit was also not considered as he continues his recovery from a shoulder injury.
"It's always unfortunate to lose players due to injury, but we have good depth in our squad and these are established players who have proven themselves at the highest level," said Springboks head coach Jacques Nienaber.
South Africa face Wales in Cardiff on 6 November, before Scotland seven days later, followed by England at Twickenham on 20 November.
Frans Malherbe (neck) and RG Snyman (knee) are also out, while the uncapped pair of lock Salmaan Moerat and scrum-half Grant Williams have been called up.
Despite De Klerk's absence there are four players in the squad from Premiership clubs - Leicester back-row forwards Jasper Wiese and Marco van Staden, Saracens prop Vincent Koch and Sale lock Lood de Jager.
New Ulster signing Duane Vermuelen is also in the squad.
Nienaber added: "The core group of players who played a key role in the series against the British and Irish Lions, as well as the Rugby Championship, will remain together as we build consistency and continuity in our squad with an eye on the 2023 Rugby World Cup."
Forwards: Thomas du Toit (Sharks), Steven Kitshoff (Stormers), Vincent Koch (Saracens), Ox Nche (Sharks), Trevor Nyakane (Bulls), Joseph Dweba (Bordeaux Begles), Malcolm Marx (Kubota Spears), Bongi Mbonambi (Stormers), Lood de Jager (Sale Sharks), Eben Etzebeth (Toulon), Salmaan Moerat (Stormers), Marvin Orie (Stormers), Siya Kolisi (captain, Sharks), Kwagga Smith (Jubilo), Marco van Staden (Leicester Tigers), Duane Vermeulen (Ulster), Jasper Wiese (Leicester Tigers) Franco Mostert (Heat)
Backs: Herschel Jantjies (Stormers), Cobus Reinach (Montpellier), Grant Williams (Sharks), Elton Jantjies (Red Hurricanes), Handre Pollard (Montpellier), Lukhanyo Am (Sharks), Damian de Allende (Munster), Jesse Kriel (Eagles), Aphelele Fassi (Sharks), Willie le Roux (Verblitz), Makazole Mapimpi (Sharks), Sbu Nkosi (Sharks), Damian Willemse (Stormers), Frans Steyn (Cheetahs)