With the increasing resistance to commonly used antimalarial drugs, different untested 'local' treatment regimens for malaria will arise. We compared commonly used treatment regimens for children in Guinea-Bissau. Symptomatic children with Plasmodium falciparum mono-infection were allocated at random to one of 4 treatments: 15 mg/kg quinine twice a day for 3 d (group 1); 10 mg/kg quinine twice a day for 3 d followed by a total dose of 25 mg chloroquine base given over 3 d (group 2); a total dose of 50 mg/kg chloroquine base given in 2 daily doses for 3 d (group 3), or sulfadoxine-pyrimethamine (group 4). On day 28 more children from group 1 (33%; relative risk [RR] = 2.9, 95% confidence interval [CI] 1.5-5.7) and group 2 (26%; RR = 2.1, CI 1.0-4.3) had had parasitaemia than in group 4 (12%), whereas no significant difference was found between group 3 (17%; RR = 1.3, CI 0.6-2.2) and group 4. No severe adverse reaction was observed in any of the groups. Chloroquine is still effective in Guinea-Bissau at an increased dose of 50 mg/kg, which appears safe when given orally in 2 daily doses for 3 d. Sulfadoxine-pyrimethamine could serve as an efficient, cheap and easy to administer second-line drug, leaving quinine to be used for third-line treatment. Quinine should not be used in short courses, nor does the combination of quinine and chloroquine have any advantage.