Combrinck gets his Bok start
Combrinck's Lions teammate Warren Whiteley (No.8) will also make his first start for the Springboks.
The inclusion of these two players are the only changes to the starting team announced by Springbok coach Allister Coetzee for the third Test against the Irish at the Nelson Mandela Bay Stadium.
Coetzee also made three changes to the bench.
Whiteley replaces the experienced Duane Vermeulen, who is out with an elbow injury, while Combrinck gets the starting nod over Lwazi Mvovo, who is now on the bench.
An ankle injury has ruled out prop Trevor Nyakane, and his place amongst the reserves is filled by the uncapped Steven Kitshoff.
He is joined on the bench by another uncapped player, Jaco Kriel, who comes into the match day squad for the first time during the series.
Adriaan Strauss will lead the Boks for the third time on Saturday, with the hooker looking to lead the South Africans to a series win over Ireland.
The series is currently tied one-all after Ireland's opening win in Cape Town and the Springboks' victory last week on the Highveld.
The Springboks have been hard at work this week to prepare themselves for what promises to be another intriguing battle between the two sides. Coetzee said the Boks are looking forward to playing the Irish in PE.
"It will be another huge battle between the sides on Saturday," said Coetzee.
"Jaco has been close to selection every time and he now gets his chance in the match day squad. Steven has worked extremely hard since we got together as a team and he also has an opportunity to show his promise should he take to the field.
"We know what is at stake on Saturday – it's a matter of winner takes all scenario. This group of players will continue to grow together as a team and Saturday they have the opportunity to gain more experience by playing together."
South Africa: 15 Willie le Roux, 14 Ruan Combrinck, 13 Lionel Mapoe, 12 Damian de Allende, 11 JP Pietersen, 10 Elton Jantjies, 9 Francois de Klerk, 8 Warren Whiteley, 7 Siya Kolisi, 6 Francois Louw, 5 Pieter-Steph du Toit, 4 Eben Etzebeth, 3 Frans Malherbe, 2 Adriaan Strauss (captain), 1 Tendai Mtawarira.
Replacements: 16 Bongi Mbonambi, 17 Steven Kitshoff, 18 Julian Redelinghuys, 19 Franco Mostert, 20 Jaco Kriel, 21 Rudy Paige, 22 Morné Steyn, 23 Lwazi Mvovo.
Date: Saturday, June 25
Venue: Nelson Mandela Bay Stadium
Kick-off: 17.00 (16.00 Ireland time; 15.00 GMT)
Referee: Glen Jackson (New Zealand)
Assistant referees: Angus Gardner (Australia), Ben Whitehouse (Wales)
TMO: Rowan Kitt (England)