Chloroquine (CQ)-resistant Plasmodium falciparum is compromising malaria control in Africa. Combining artesunate (AS) with standard antimalarial drugs increases cure rates and may delay drug resistance. We compared the safety and efficacy of CQ alone and CQ combined with AS (CQ-AS) for treating uncomplicated P. falciparum malaria in Burkina Faso between August 1999 and August 2000. Chloroquine (25 mg/kg over 3 d) combined with AS or placebo (4 mg/kg/d for 3 d) was administered to 300 children aged 6 to 59 months in a randomized, double-blind study. Follow-up extended over 28 d. No adverse drug reactions were recorded. By day 14, parasites were cleared in 120/147 (81.6%) CQ AS-treated children compared with 53/143 (37.1%) CQ-treated children (odds ratio [OR] = 7.55, 95% CI 4.27-13.43, P < 0.001). Corresponding rates for day 28 were 71/145 (49.0%) vs. 27/142 (19.0%) (OR= 4.09, 95% CI 2.33-7.21, P < 0.001). Children who received CQ-AS had significantly faster parasite and fever clearance. Despite the beneficial effects of adding AS, the high failure rate at day 28 of CQ-AS precludes its use as the first-line regimen for treating CQ-resistant P. falciparum in Burkina Faso.