England lost Alastair Cook early in pursuit of 221 needed to win the fourth NatWest Series match at Lord's and take a 2-1 lead over South Africa.
As in their victory at The Oval two days ago, off-spinner James Tredwell (three for 35) and all-rounder Ravi Bopara proved to be among the hosts' most effective bowlers as South Africa mustered 220 for eight.
On a pitch offering turn and occasional variable bounce, England, who were 58 for one after 15 overs, gave themselves an obvious chance of a successful chase but not one which yet represented a foregone conclusion.
It was still less so once captain Cook, enduring a lean run of scores in both one-day internationals and Tests, took his sequence without a half-century to nine innings when he was lbw in the first over to a very good delivery from Dale Steyn which came back up the slope to beat the left-hander's forward-defence.
Steyn continued to find movement in the air and off the pitch, under persistently cloudy skies and floodlights, and Ian Bell and Jonathan Trott did well to avoid further losses in an unbroken half-century stand.
A 10.15am start had earlier increased the significance of the toss, and South Africa openers Hashim Amla and Graeme Smith were required to be conservative.
After three wickets then fell for the addition of only 15 runs in the middle overs, more caution was necessary for the tourists from 115 for four in the 29th. AB de Villiers and Dean Elgar could not avoid to be flashy, their half-century stand spanning a batting powerplay which brought just 24 runs in an innings that went 13 overs without a boundary.
Amla was yet again the scourge of England's bowlers, and fielders, on his way to South Africa's modest top score of 45.
England dropped the prolific batsman for the sixth time this summer, on four, when Tredwell failed to hang on to a sharp chance away to his right at second slip off Steven Finn.
But after Smith had edged an attempted pull at Jade Dernbach behind - to end a stand of 68, and ensure Tredwell did not pay too dearly for another drop at slip - Bopara twice took the fielders, and the umpire, out of the equation. He swung one back between Amla's bat and pad, to beat the attempted drive, and hit off-and-middle - and then had Faf du Plessis chopping on for just a single.