New Zealand-born Hadleigh Parkes will make his Wales debut in Saturday's Principality Stadium clash against South Africa.
The Scarlets centre only completes a three-year Wales residency qualification this week, but head coach Warren Gatland has handed him an immediate opportunity alongside Scott Williams in midfield.
Parkes is one of five changes from the team beaten by world champions New Zealand last weekend for Wales' Under Armour Series finale.
— Welsh Rugby Union (@WelshRugbyUnion) November 30, 2017
Elsewhere, Scarlets scrum-half Aled Davies earns a surprise opportunity, with Rhys Webb, who suffered a head knock against world champions New Zealand last weekend and has been following return-to-play protocols, on the bench and Davies' fellow Scarlets number nine Gareth Davies not in the match-day 23.
A back injury sidelines hooker Ken Owens, so Cardiff Blues' Kristian Dacey starts, while Dragons lock Cory Hill replaces dislocated shoulder victim Jake Ball and Bath's on-loan Blues prop Scott Andrews also features.
And Bath number eight Taulupe Faletau remains on starting XV duty, despite four other Aviva Premiership-based players - Owen Williams, Jamie Roberts, Rhys Priestland and Tomas Francis - returning to their clubs as the Springboks encounter falls outside World Rugby's autumn Test window.
England's Premiership clubs have a blanket approach not to release players for those games.
While that policy remains unchanged and in force this week, it is understood that Faletau has a clause in his club contract giving him full release for Wales. But Bath can still expect a fine after Northampton took a GBP60,000 hit for releasing Wales wing George North to face Australia outside the 2013 autumn window.
With Exeter prop Francis unavailable and his fellow tighthead Leon Brown (concussion) sidelined, Andrews makes a first Wales start since a two-Test Japan tour four years ago.
Ospreys forward Rhodri Jones, meanwhile, has been summoned from outside the Wales squad to provide front-row bench cover - he reported for training earlier this week - as Wales target a third successive home victory over South Africa.
Only Scarlets prop Wyn Jones remains from the replacements selected for New Zealand, with Scarlets back Rhys Patchell among those who could get an opportunity this weekend.
Parkes, 30, has trained with the Wales squad this month in preparation for his expected involvement against the Springboks, and he will hope to transfer consistently-impressive Scarlets form into the Test arena.
Wales' autumn campaign so far has realised losses to Australia and New Zealand, plus an unconvincing 13-6 victory over Georgia.
And the Springboks encounter is their final game before a testing NatWest 6 Nations opener against an in-form Scotland on February 3.
"Saturday is an opportunity to continue to build on what we have done so far and round off the autumn campaign with a big performance," Gatland said.
"We have spoken about exposing the squad to Test match rugby, and this weekend is a great opportunity for Hadleigh to earn his first cap and for Aled to make his first start of the campaign.
"We have had a couple of knocks from last weekend, with Ken, Leon and Jake unavailable, but that just provides an opportunity for Kristian, Scott and Cory to start."
Wales team to play South Africa
Forwards: 1 Rob Evans (Scarlets), 2 Kristian Dacey (Cardiff Blues), 3 Scott Andrews (Cardiff Blues), 4 Cory Hill (Dragons), 5 Alun Wyn Jones (CAPTAIN, Ospreys), 6 Aaron Shingler (Scarlets), 7 Josh Navidi (Cardiff Blues), 8 Taulupe Faletau (Bath)
Backs: 9 Aled Davies (Scarlets), 10 Dan Biggar (Ospreys), 11 Steff Evans (Scarlets), 12 Hadleigh Parkes (Scarlets)*, 13 Scott Williams (Scarlets), 14 Hallam Amos (Dragons), 15 Leigh Halfpenny (Scarlets)
Replacements: 16 Elliot Dee (Dragons), 17 Wyn Jones (Scarlets), 18 Rhodri Jones (Ospreys), 19 Seb Davies (Cardiff Blues), 20 Dan Lydiate (Ospreys), 21 Rhys Webb (Ospreys), 22 Rhys Patchell (Scarlets), 23 Owen Watkin (Ospreys)
* Denotes uncapped player