Combining artesunate with existing antimalaria drugs may improve cure rates, delay emergence of resistance, and reduce transmisison. We performend a randomized comparative trial to quantify the effect of adding artesunate to sulfadoxine-pyrimethamine in the treatment of uncomplicated falciparum malaria in Indonesia. Using a modified 1997 World Health Organization protocol for assessment of therapeutic efficacy of antimalaria drugs, 105 patients (stratified by age/ethnic group) were randomized: 53 received artesunate orally 4 mg/kg of body weight, a single daily dose for three days, plus sulfadoxine-pyrimethamine orally (1.25 mg of pyrimethamine/kg of body weight), a single dose on day 0 and 52 patients received sulfadoxine- pyrimethamine alone. Six from the combination group were withdrawn from analysis, as were six of the sulfadoxine-pyrimethamine group. Treatment failure rates on day 14 were 0%in the artesunate plus sulfadoxine-pyrimethamine group and 8.7% in the sulfadoxine-pyrimethamine group (P=0.12). Treatment failure rates on day 28 were 4.4% and 15.2%, respectively (P=0.16). Relative risk of treatment failure at 28 day was 0.3 (95% confidence inteval [CI]=0.1&#8211;1.3). Mean fever clearance time (1.3 versus 1.7 days) and mean parasite clearance time (1.4 versus 2.0 days) were both faster in the artesunate plus sulfadoxine-pyrimethamine group than in the sulfadoxine-pyrimethamine group ( P=0.08 and P < 0.0001, respectively). Only 20 (39.2) of 51 patients treated with artesunate plus sulfadoxine-pyrimethamine were still parasitemic on day 1 compared with 45 (86,5%) of 52 patients treated with sulfadoxine-pyrimethamine alone (P = 0.000001, relative risk [RR]=0.4,95% CI=0.3-0.6). Gametocyte carriage was lower following artesunate plus sulfadoxine-pyrimethamine than following sulfadoxine-pyrimethamine (RR=0.5, 95% CI=0.2-1.0 on day 7 and RR = 0.5, 95% CI=0.2-1.1 on day 14 ). Mild diarrhea, rash and itching resolved without treatment. Combined artesunate plus sulfadoxine- pyrimethamine resulted in more rapid fever and parasites clearance, was well tolerated, reduced risk of treatment failure, and lowered gametocyte carriage.