Wales' long wait to claim the major southern hemisphere scalp they crave continues - but only after an heroic display in a ferocious Test match of brutal intensity at the Millennium Stadium.
The reigning RBS 6 Nations champions lost four players with injuries during an unforgiving first half - Liam Williams (head), Jonathan Davies (shoulder), Adam Jones (calf) and Scott Andrews (neck) - yet they did not fold.
Five Leigh Halfpenny penalties kept them in the contest, but early Springboks tries by skipper Jean de Villiers and hooker Bismarck du Plessis made the difference, while fly-half Morne Steyn - he was another early injury victim - converted both touchdowns and booted a penalty.
The clinching try came 15 minutes from time, scored by scrum-half Fourie du Preez when he capitalised on defensive hesitancy between Halfpenny and Rhys Priestland, and full-back Pat Lambie's conversion finished Wales off.
Wales have claimed just one win from 22 starts against southern hemisphere heavyweights South Africa, New Zealand and Australia since coach Warren Gatland took charge more than five years ago.
And their latest failure once again left them with a feeling of what might have been. Wales gave it everything, but South Africa's streetwise approach and greater finishing power ultimately proved too much.
Wales now move on to face Argentina, Tonga and Australia, although Gatland's first task will be to assess an horrendous casualty count before regrouping for the Pumas' visit next Saturday.
Despite the stadium roof being closed, what appeared to be a poor playing surface showed signs of cutting up even during the warm-ups, suggesting it had not fully recovered from staging back-to-back Rugby League World Cup games two weeks ago.
It proved no distraction to Wales, though, and they made a blistering start as Halfpenny kicked two penalties inside the opening seven minutes, both following sharp midfield breaks by centre Davies.
Halfpenny's second successful strike took him to 300 points for Wales, but South Africa quickly found their rhythm following a Steyn penalty as they stunned Wales with a breathtaking try.
Wing Bryan Habana left the home defence for dead when he broke clear from inside his own half, and the supporting Du Plessis sent De Villiers over before Steyn slotted the conversion.
And it came at a heavy cost for Wales, as Williams - who was a late call-up for hamstring victim Eli Walker - and Davies both departed with injuries suffered during South Africa's try-scoring move.
James Hook replaced Williams, moving to full-back duty and Halfpenny switching to the wing, while Ospreys centre Ashley Beck took over from Davies, but South Africa scored their second try while Wales regrouped.
Du Plessis was the beneficiary of some quality close-quarter work by South Africa's forwards, powering over the line, and Steyn again converted before he departed injured during a brutal opening quarter that had taken its toll.
Wales appeared visibly stunned by the ferocity of South Africa's play, especially at the breakdown, but a third Halfpenny penalty just about kept them in contention.
Halfpenny further narrowed the deficit with another immaculate strike, and Wales suddenly regained their early dominance, helped by taking a temporary one-man advantage when Springboks flanker Francois Louw was sin-binned.
Referee Alain Rolland, the official who controversially sent off Wales skipper Sam Warburton during the 2011 World Cup semi-final, consulted his television match official Eric Gauzins before brandishing a yellow card.
Replays showed that Bath forward Louw led with his forearm into Wales hooker Richard Hibbard's face at a ruck, but Rolland took the sin-bin option.
A breathless opening 40 minutes ended with South Africa five points ahead, which represented an impressive revival by a Welsh team that could easily have folded, such was their first-half injury toll.
Andrews' contribution lasted only until the interval before he was forced off due to a neck problem, and Bath prop Paul James replaced him for the second period.
But Wales kept plugging away, not conceding an inch at the set-pieces and making one crunching tackle after another, before Halfpenny's fifth penalty from five attempts set up a pulsating final quarter.
The game then took an unexpected twist, going to uncontested scrums for 10 minutes after Rolland sin-binned rival props Gethin Jenkins and Coenie Oosthuizen. By using his yellow card, though, it could be argued that Rolland made a rod for his own back.
Wales had no more props to bring on, hence the unedifying uncontested episode, and Du Preez struck with both teams still down to 14, confirming South Africa's 25th win from 27 starts in a fixture that stretches back 107 years.