South Africa will start with three debutants against England on Saturday, potentially changing their entire XV as they wait on Trevor Nyakane's fitness.
Director of rugby Rassie Erasmus' first game in charge ended in defeat to Wales in the United States last week, as a bizarre late try cost the Springboks victory.
After fielding an experimental side for that match, Erasmus has lined up a completely different outfit for the clash with England, with only Wilco Louw possibly keeping his place if Nyakane - struggling with a rib injury - is not fit to start.
S'busiso Nkosi and Aphiwe Dyantyi will make their bows on the wings, while lock RG Snyman has also been handed a first cap as Siya Kolisi begins his stint as captain.
Erasmus said: "We have some good experienced players, while there are some really exciting young men who have earned their opportunity to play for the Springboks.
"I am especially pleased for the three newcomers, Aphiwe, Sbu and RG. I am looking forward to see how they will perform in tough Test match conditions against a formidable opponent."
South Africa are set to take a call on Nyakane's fitness on Friday. If he is declared unavailable, Louw will start with Thomas du Toit taking his place on the bench.
South Africa: Willie le Roux, S'busiso Nkosi, Lukhanyo Am, Damian de Allende, Aphiwe Dyantyi, Handre Pollard, Faf de Klerk; Tendai Mtawarira, Bongi Mbonambi, Trevor Nyakane or Wilco Louw, RG Snyman, Franco Mostert, Siya Kolisi, Jean-Luc du Preez, Duane Vermeulen.
Replacements: Akker van der Merwe, Steven Kitshoff, Wilco Louw or Thomas du Toit, Pieter-Steph du Toit, Sikhumbuzo Notshe, Ivan van Zyl, Elton Jantjies, Warrick Gelant.