The increasing occurrence of chloroquine-resistant Plasmodium falciparum in sub-Saharan Africa makes it essential to reconsider current recommendations for the treatment of uncomplicated P.falciparum malaria. In an open, randomized trial, we have compared chloroquine (CQ), amodiaquine (AQ), and pyrimethamine-sulphadoxine (PS) in rural Gambian children with uncomplicated P.falciparum malaria. Three hundred children were randomly assigned at the time of consultation (Do) to oral treatment with 25 mg/kg CQ, 25 mg/kg AQ (both given over 3 days), or 1.25/25 mg/kg PS. They were reviewed on day 7 (D7) and day 28 (D28) for symptoms, malaria parasitaemia, and packed cell volume (PCV). Significantly more children treated with PS compared to CQ (17 vs 7%, P = 0.03) or AQ (17 vs 3%, P = 0.001) returned with clinical complaints during the first 3 days after treatment. Five of these patients had a generalized convulsion (1 from the AQ group, 4 from the PS group), of whom 4 developed cerebral malaria. At D7, significantly more patients treated with CQ compared to AQ (25 vs 7%, P = 0.0009) or PS (25 vs 4%, P = 0.0001) were parasitaemic. By D28, the cumulative number of parasitological failures was significantly higher in the CQ group compared to the AQ group (65 vs 35%, P = 0.0001), and significantly higher in the AQ group compared to the PS group (35 vs 14%, P = 0.001). Overall, 91% of parasitological failures observed during the study period were symptomatic and were consequently treated with an alternative antimalarial drug. Over the 28-day study period the mean PCV increased significantly less in the CQ group than in the PS group (1.2 vs 3.8%, P = 0.016) and was lower in the CQ group than in the AQ group (1.2 vs 2.7%, P = 0.12, not significant). These results suggest that PS acts more slowly than 4-aminoquinolines in controlling the clinical features of malaria, and that AQ can be considered as an interim alternative to CQ in the first-line therapy of uncomplicated malaria in African areas of high CQ resistance.