The World Champions beat the Lions 2-1 last summer in a series in which every single Springbok player plied his trade in his homeland.
The Boks have traditionally employed a policy of only selecting South African-based players in Test squads but that changed last autumn when a trio of Irish-based players were called up during an unsuccessful tour of Europe.
Munster's Jean de Villiers, Ulster's BJ Botha and Leinster's CJ Van Der Linde are all included for the Millennium Stadium encounter on June 5, as are French-based stars Frans Steyn and Joe Van Niekirk and Bath's Butch James.
James in particular had made no attempt to hide his desire to face the Lions 12 months ago but his absence from domestic competition cost him his chance to face Britain and Ireland's elite.
The side that will arrive in the Welsh capital on June 5 bears almost no resemblance to the one that faced the Lions.
Only skipper John Smit, Ruan Pienaar, de Villiers and Steyn started the first Test against Sir Ian McGeechan's tourists, with an all-South African Super 14 final and a desire to rest a number of star players resulting in a greatly-weakened Bok side.
James starts in the unfamiliar position of inside centre, while there are two new caps in flanker Francois Louw and South Africa Sevens wing Gio Aplon and a recall for former Ospreys scrum-half Ricky Januarie.
"We have had a few challenges with two of our sides in the Super 14 playoffs but we have still been able to assemble a very talented squad," said Bok head coach Peter de Villiers.
"Nevertheless we have picked a few Bulls and Stormers players who we believe have earned their places through hard work and consistency.
"Only Butch (James) and Big Joe (van Niekerk) have not played since 2008 but they are both quality players who have been in good form for their clubs.
"Butch offers versatility in that he can play at fly-half and he brings a physical edge to the defence, which we will need against Wales.
"Joe has been one of the top loose forwards in France for the past two seasons and in our discussions with him recently he has said he is raring to go.
"The Welsh are up for this one. They have a strong squad with a few young guns who will be eager to prove themselves.
"With only a week to prepare for this Test we are going to structure our training sessions very carefully to make sure that we focus our attentions on the right areas, with defence being one of the most critical.
"There is also the fact that this team has not played together before but we are not looking for excuses, we are accepting the challenge."
South Africa matchday squad to face Wales
Frans Steyn (Racing Metro); Gio Aplon (Stormers), Jean de Villiers (Munster), Butch James (Bath), Odwa Ndungane (Sharks); Ruan Pienaar (Sharks), Ricky Januarie (Stormers); CJ van der Linde (Leinster), John Smit (Sharks, capt), BJ Botha (Ulster), Danie Rossouw (Bulls), Andries Bekker (Stormers), Francois Louw (Stormers), Dewald Potgieter (Bulls), Joe van Niekerk (Toulon)
Replacements: Chiliboy Ralepelle (Bulls), Jannie du Plessis (Sharks), Alistair Hargreaves (Sharks), Ryan Kankowski (Sharks), Meyer Bosman (Cheetahs), Juan de Jongh (Stormers), Bjorn Basson (Cheetahs)