JP Pietersen will win his 50th cap for South Africa when the Springboks face Scotland, with Pat Lambie and Bakkies Botha both starting.
The 27-year-old Pietersen, who will return from Japan to Durban to play for the Sharks in Super Rugby next season, made his Test debut on 9 September 2006 against Australia in Johannesburg when he was only 20.
Pietersen, a Rugby World Cup winner in 2007, will become the fifth player this season to earn his 50th Test cap for South Africa. Only two other wingers, Bryan Habana and Breyton Paulse, have reached this milestone for the Springboks.
"This is really a magnificent achievement for one of the many world-class wingers South African rugby has produced," said Springbok coach Heyneke Meyer.
"For more than seven years, JP has been one of the most consistent players for the Springboks. He always gives everything he has for his country and this is just reward for the hard work and dedication he's put in over the years. Was it not for injuries, JP would probably have played many more Tests for South Africa"
As anticipated, Meyer made a total of five changes to the starting line-up, while two more are possible because of injury niggles.
In the tight five, Bakkies Botha returns for the first time since the Rugby World Cup in New Zealand in 2011, while Gurthrö Steenkamp and Adriaan Strauss will start at Murrayfield. Eben Etzebeth, Tendai Mtawarira and Bismarck du Plessis are on the bench.
In the backs, Willie le Roux takes over at full-back with Pat Lambie shifting to fly-half. A final call on the availability of Morné Steyn (back) and Willem Alberts (shoulder) will be made on Saturday.
If Alberts is unfit to start, Siya Kolisi will take his place on the side of the scrum. Marcell Coetzee has been included on the bench in another rotational change with Kolisi, who will sit out if Alberts is passed fit. Steyn has been included on the bench pending a fitness test on Saturday.
"We said from the start of the tour that we were going to make a few changes for this Test," added Meyer.
"We need to keep players fresh and motivated. Willie and Pat both did well after we lost Morné last weekend and deserve another opportunity on Sunday.
"Gurthrö and Adriaan, who will take over the vice-captaincy as well, have been part of the squad for a long time and will slot in easily. Furthermore, it has been great to have Bakkies back. His enthusiasm has been contagious and the younger guys have already learned a lot from spending time with him.
"We got our tour off to a good start last week against Wales in Cardiff and the focus this week has been on further improvement in a number of key areas of the game, most notably our discipline.
"In the Rugby Championship, we conceded the fewest penalties, but last week against Wales we were penalised too much. It's something that is very important to us and we are working very hard on our discipline."
South Africa: 15 Willie Le Roux, 14 JP Pietersen, 13 Jaque Fourie, 12 Jean de Villiers, 11 Bryan Habana, 10 Patrick Lambie, 9 Fourie du Preez, 8 Duane Vermeulen, 7 Willem Alberts/Siya Kolisi, 6 Francois Louw , 5 Flip van der Merwe, 4 Bakkies Botha, 3 Frans Malherbe, 2 Adriaan Strauss, 1 Gurthrö Steenkamp.
Replacements: 16 Bismarck du Plessis, 17 Tendai Mtawarira, 18 Coenie Oosthuizen, 19 Eben Etzebeth, 20 Marcell Coetzee, 21 Ruan Pienaar, 22 Morné Steyn, 23 JJ Engelbrecht.
Date: Sunday, November 17
Venue: Murrayfield, Edinburgh
Kick-off: 15:00 GMT (17.00 SAST)
Referee: Jérôme Garcès (France)
Assistant referees: Pascal Gauzère (France), Dudley Phillips (Ireland)