Harlequins were the first victims of a South African side in the Heineken Champions Cup as the Sharks held on for a bonus-point victory in Durban.
Josh Bassett's second try got Quins to within one point of victory with five minutes remaining.
But Boeta Chamberlain scored to seal the win and take a losing bonus point away from the visitors.
Sharks went down to 13 players after Bongi Mbonambi was shown a yellow card and Ox Nche a red with 20 minutes left.
Andre Esterhuizen scored two tries but that was only enough to give Harlequins a four-try bonus point.
Sharks became the first South African side to play in the previously European club competition and are joined in the Champions Cup by Stormers and Bulls.
Sharks hold off Quins revival
With Springbok stars Siya Kolisi, Eben Etzebeth and Makazole Mapimpi in the Sharks side, Harlequins may well have been expecting a tough day in Durban.
But the visitors - playing without injured England fly-half Marcus Smith - defied expectations with an early try as they caught Sharks' defence too narrow, leaving space for Bassett to go over.
Harlequins' pace clattered into the Sharks' up-front dominance and that soon paid dividends for the hosts as Mbonambi scored on the back of a maul.
A Curwin Bosch penalty put the South African side ahead and they would not relinquish that lead for the rest of the match as wing Mapimpi showed his side could be fleet of foot too with his two tries.
Will Evans went over in a maul to trim the deficit to eight points before the break and give the travelling fans hope, but Werner Kok soon quelled that as he chased his own kick to score in the second 40.
A Quins comeback looked possible as Mbonambi was sent to the sin-bin for repeated infringements at the breakdown and Nche went off for a high tackle on Jack Walker.
After Bosch added an extra three-point cushion, former Shark Esterhuizen claimed his two tries and set up Bassett for another to get within one point of a superb victory before Chamberlain closed out the win for the hosts.
Quins have three more fixtures to play in the group stage, hosting Sharks before playing French side Racing 92 home and away.
Cell C Sharks: Chamberlain; Kok, Venter, Tapuai, Mapimpi; Bosch, Hendrikse; Nche, Mbonambi, Sadie, Etzebeth, Grobler, Kolisi (c), Tshituka, Buthelezi.
Replacements: Jooste, N Mchunu, K Mcunhu, Andrews, Notshe, Williams, Cronhe, Van Rensburg
Harlequins: David; Murley, Marchant, Esterhuizen, Bassett; Allan, Care; Marler, Walker, Louw, Lamb, Herbst, Kenningham, Evans, Dombrandt (c)
Replacements: Head, Baxter, Kerrod, Hammond, Lawday, Gjaltema, Beard, Edwards