South Africa secured their first win under coach Rassie Erasmus and extended England's losing streak with a thrilling 42-39 triumph in Johannesburg.
England took off in the opening stages at Ellis Park, scoring three superb tries as they flew out to a 24-3 lead after just 18 minutes.
Yet their advantage disappeared before the break, debutant winger Sibusiso Nkosi crossing twice as South Africa turned the game around to sit 29-27 in front at the break.
The second half failed to match the first in terms of points but England could not avoid a fourth successive Test defeat, a miserable run of form that increases the pressure on coach Eddie Jones just over a year out from the 2019 World Cup.
The two nations go head-to-head again in the second Test in Bloemfontein next Saturday before rounding out the series in Cape Town on June 23.
If Jones' squad were feeling the pressure after their miserable recent run, they certainly did not show it during a blistering start.
After Elliot Daly opened the scoring with a penalty from inside his own half, Mike Brown - starting on the wing, rather than at full-back - broke free from two tacklers to wriggle over in the left corner.
The Springboks briefly responded with three points from the boot of Handre Pollard, only to be hit with a quick one-two that left them reeling on the ropes.
Jonny May's well-timed pass put Daly into space on England's left before the latter turned provider on the opposite flank for Owen Farrell, throwing a simple inside ball to set his captain scampering clear next to the posts.
However, South Africa climbed off the canvas, Faf de Klerk plunging over from close range before Nkosi's brace, although the first owed much to Daly's failure to deal with a bouncing ball inside his own in-goal area.
When the outstanding Willie Le Roux cruised over, with Pollard adding his third conversion, the Boks had blitzed 26 points in the space of 20 eventful minutes.
Farrell kicked a penalty to make it 29-27 before a much-needed interval, giving both players, coaching staff and also spectators the chance to draw breath at altitude.
Unsurprisingly, the break also put an end to the points spree. Pollard extended South Africa's advantage with a penalty, though the fly-half's effort was sandwiched between two misses that kept England in touch.
Mako Vunipola marked his 50th Test appearance with a trip to the sin bin for a late challenge on De Klerk, with the hosts quickly making the most of the extra man with a try out wide for debutant winger Aphiwe Dyantyi.
England tried to match South Africa's first-half comeback in the closing stages, Maro Itoje reaching over the top of a ruck to score before May raced clear from inside his own territory, but the hosts held on to edge a classic.