Abstract: The objective of the study was to evaluate the tolerability and efficacy of cotrimoxazole plus amodiaquine (aqct) in the treatment of Plasmodium falciparum malaria and to compare efficacy of this combination with that of pyrimethamine-sulphadoxine plus amodiaquine (aqsp) in an area of high malaria transmission. Children aged between 6 months and 10 years with clinical and parasitological evidence of Plasmodium falciparum malaria were randomized to receive either of cotrimoxazole plus amodiaquine or pyrimethamine-sulphadoxine plus amodiaquine. Ninety seven children (51 and 46, respectively, in the cotrimoxazole plus amodiaquine group and pyrimethamine-sulphadoxine plus amodiaquine group) completed the study per protocol and were evaluated. Pre treatment clinical and parasitological parameters were similar in the 2 treatment groups. The time to clear fever and other symptoms were similar in the two groups 1.64±0.98 vs 1.47±0.74; p>0.05. Parasite clearance times were also similar; 2.41±0.67 vs 2.35±0.60 days, respectively, for aqct and aqsp; p>0.05. The cure rates on days 14, 21 and 28 were, respectively, 98, 94 and 87% for aqct and 100, 98 and 89% for aqsp treatment groups. The combination of amodiaquine-cotrimoxazole has potentially negative effect on gametocytogenesis. Both drugs were well tolerated. These results indicate that cotrimoxazole plus amodiaquine has similar efficacy to pyrimethamine-sulphadoxine plus amodiaquine in the treatment of acute uncomplicated Plasmodium falciparum malaria in children resident in an endemic area of Southwest Nigeria.