Injured World Rugby Player of the Year Pieter-Steph du Toit was released on Sunday from the South Africa squad preparing for their first four matches of the season, a SA Rugby statement said.
The 32-year-old flanker/lock, who plays for Japanese club Toyota Verblitz, is among six injured players who will not feature against the Barbarians, Italy (twice) and Georgia from June 28 to July 19.
Props Gerhard Steenekamp and Ntuthuko Mchunu, number 8s Juarno Augustus and Cameron Hanekom and centre Lukhanyo Am have also been released due to injuries.
Augustus, who joins Ulster next season after helping Northampton Saints reach the Champions Cup final, will be particularly disappointed as he had received his first call-up from the record four-time Rugby World Cup winners.
The statement did not specify what injuries the players have, nor did it indicate when they might be available for selection, with South Africa set to play 14 matches this year.
Coach Rassie Erasmus has reduced his squad from 55 to 45 ahead of the first outing, a non-cap exhibition match against the Barbarians in Cape Town on June 28.
Apart from the six injured players, the Hendrikse brothers, fly-half Jordan and scrum-half Jaden, flanker Renzo du Plessis, full-back Quan Horn and wing/full-back Ntokozo Makhaza have been omitted.
Makhaza, a 23-year-old university student based in Cape Town, was a surprise inclusion in the original squad as he has never played at senior level.
Erasmus has added one player, uncapped prop Boan Venter, who joined Edinburgh from Bloemfontein franchise the Cheetahs.
"Boan has been consistent for Edinburgh in the United Rugby Championship and Challenge Cup," said Erasmus, coach of the 2019 World Cup-winning team and director of rugby when the Springboks triumphed in France four years later.
"He is familiar with the South African structures after playing for the Cheetahs and coming through our junior ranks, so we are looking forward to seeing him in action."
After the Barbarians match, South Africa meet Italy in Pretoria on July 5 and in Gqeberha on July 12, then Georgia in Mbombela on July 19.
The Springboks play two Rugby Championship tests each against Australia, New Zealand and Argentina between August and October.
Tour matches against France, Italy, Ireland and Wales in November complete their schedule. However, there could be additional fixtures as Erasmus has said he would like to play two extra tests this year.