England (6) 28
Try: Wilson, Morgan, Barritt
Pens: Farrell 3
Conversions: Farrell 2
South Africa (13) 31
Try: Serfontein, Reinach, Burger
Pens: Lambie 3
Conversions: Lambie 2
Drop goals: Lambie
England's suffered a fifth straight defeat for the first time for 30 years to leave their World Cup preparations in tatters after being overwhelmed by South Africa at Twickenham.
Jan Serfrontein, Cobus Reinach and Schalk Burger's tries and 16 points from the boot of Pat Lambie stretched the Springboks' unbeaten record against England to 12 matches to inflict upon Stuart Lancaster's side their second straight of their autumn campaign.
But after a fighting display against New Zealand a week previous, England produced an uncertain and at times ragged showing which was summed up by Dylan Hartley's yellow card for aggressive stamping at a maul.
After David Wilson and replacement Ben Morgan's tries had drawn England level at 20-20, Brad Barritt's late scores did give the home side late hope but they fell short by three-points for a second successive weekend.
Meanwhile, victory for South Africa acts as the perfect tonic following the defeat to Ireland and further enhances their claim as one of the central contenders to win a third World Cup in less than a year.
Following respective defeats to New Zealand and Ireland last weekend, both England and South Africa knew only victory would reignite their autumn campaign and boost their status as World Cup contenders in 11 months time.
Injury to Semesa Rokoduguni allowed Bath teammate Anthony Watson to make his first international start in the only change from the 21-24 loss to the All Blacks, with Marland Yarde returning to the matchday 23. Danny Care won his fiftieth cap at scrum half.
Heyneke Meyer meanwhile rung the changes from the loss in Dublin, recalling wing JP Pietersen - who had four tries in his seven appearances against England - while returning flanker Burger bolstered a pack which included Eben Etzebeth and IRB player of the year nominee Duane Vermeulen.
After a spirited display against the world No.1 ranked side a week previous, England started in lacklustre fashion and as they struggled to break down their stubborn visitors, Owen Farrell's risky pass inside his own 22 allowed South Africa to take the lead through Lambie's penalty.
And further inaccuracy with the ball in hand from England's half-backs contributed to the Springboks scoring the opening try, as a telegraphed pass from Care was intercepted by Serfontein, who ran under the posts for his second international score.
Breaks from Mike Brown and Billy Vunipola did give England encouragement but continual South Africa turnovers - prowess they showed during the recent Rugby Championship - delayed their attempts to cut the advantage until Farrell's penalty rewarded a belated first half charge.
Lambie and Farrell exchanged penalties to keep the lead at seven, though if England felt they were in touch at the break it took just 50 seconds for their mood to change as South Africa stuck with devastating effect.
Lambie's kick over a high England line found the onrushing Willie le Roux and his offload released Reinach who went over to cap a stunning and clinical move from the two-time World Cup winners.
But that position of authority was quickly washed away, as Victor Matfield's yellow card for collapsing a maul sparked a stunning England fightback as first Wilson and then substitute Morgan went over after surging drives from the hosts' pack.
However, with Matfield due to return England's comeback was stifled as South Africa claimed their third try of the afternoon with 14-men as a catch and drive of their own was finished off by Burger.
The challenge facing Lancaster's team was then further accentuated when Hartley was adjudged to have stamped aggressively at a rolling maul, earning a yellow card and taking England's hopes with him.
Lambie's penalty was followed by successive kicks from Farrell, scores which gave England new impetus, as they restored to 15 men, heading into the final 10 minutes with South Africa protecting just a five-point lead.
However, two further penalties for Lambie, despite Barritt's late score, meant England fell short by three points for a second week in a row to give coach Lancaster food for thought ahead of the final two internationals against Samoa and Australia.
England: 15. Mike Brown; 14. Anthony Watson, 13. Brad Barritt, 12. Kyle Eastmond, 11. Jonny May; 10. Owen Farrell, 9. Danny Care; 1. Joe Marler, 2. Dylan Hartley, 3. Dave Wilson, 4. Dave Attwood, 5. Courtney Lawes, 6. Tom Wood, 7. Chris Robshaw (captain), 8. Billy Vunipola.
Replacements: 16. Robert Webber, 17. Matt Mullan, 18. Kieran Brookes, 19. George Kruis, 20. Ben Morgan, 21. Ben Youngs, 22. George Ford, 23. Marland Yarde.
South Africa: 15. Willie le Roux; 14. JP Pietersen, 13. Jan Serfontein, 12. Jean de Villiers (captain), 11. Bryan Habana; 10. Pat Lambie, 9. Cobus Reinach; 1. Tendai Mtawarira, 2. Adriaan Strauss, 3. Jannie du Plessis, 4. Eben Etzebeth, 5. Victor Matfield, 6. Marcell Coetzee, 7. Schalk Burger, 8. Duane Vermeulen.
Replacements: 16. Bismark du Plessis, 17. Trevor Nyakane, 18. Coenie Oosthuizen, 19. Bakkies Botha, 20.Teboho Mohoje, 21. Francois Hougaard, 22. Handre Pollard, 23. Cornal Hendricks.