Background: The case fatality rate of severe malaria remains unacceptably high. N‐acetylcysteine (NAC) is a safe compound that inhibits tumour necrosis factor (TNF) and impedes cytoadherence, both of which have been implicated in the pathogenesis of malaria complications. Aim: To evaluate NAC as adjunctive therapy in severe malaria. Design: A placebo‐controlled, double‐blind prospective study, with serum lactate level as the principal objective measure of response. Methods: Thirty adult males with severe, quinine‐treated malaria received either 300 mg/kg of NAC or placebo, over 20 h. Results: Serum lactate levels normalized twice as quickly after NAC (median 21 h, 95%CI 12–36 h) as after placebo (median 42 h, 95%CI 30–84 h; p=0.002, Mann–Whitney U test). Twenty‐four hours after admission, 10/15 (67%) NAC‐group patients but only 3/15 (20%) placebo‐group patients had normal lactate concentrations (p=0.01, Fisher exact test). NAC‐treated patients could be switched from intravenous to oral therapy earlier than individuals who received placebo (42 h vs. 51 h after admission) but the difference was not significant (p=0.28, Mann–Whitney U test). Discussion: NAC's mechanism of action in malaria is unclear, since it did not markedly alter plasma cytokine profiles. Trials of NAC adjunctive therapy for complicated malaria, with mortality as an endpoint, appear to be warranted.