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In Malawi, trimethoprim-sulfamethoxazole (TS) is the recommended first-line treatment for children with Integrated Management of Childhood Illness dual classifications of malaria and pneumonia, and sulfadoxine-pyrimethyamine (SP) plus five days of treatment with erythromycin (SP plus E) is the recommended second-line treatment. Using a 14-day, modified World Health Organization protocol, children with dual IMCI classifications of malaria and pneumonia with Plasmodium falciparum parasitemia were randomized to receive TS or SP plus E. Clinical and parasitologic responses and gametocytemia prevalence were obtained. A total of 87.2% of children receiving TS and 80.0% receiving SP plus E reached adequate clinical and parasitologic responses (ACPRs) (P = 0.19). Severely malnourished children were less likely to achieve ACPRs than those better nourished (relative risk = 3.34, P = 0.03). Day 7 gametocyte prevalence was 55% and 64% among children receiving TS and SP plus E, respectively (P = 0.19). Thus, TS and SP plus E remain efficacious treatment of P. falciparum malaria in this setting. However, patient adherence and effectiveness of five days of treatment with TS is unknown.