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The choice of appropriate artemisin-based combination therapy depends on several factors (cost, efficacy, safety, reinfection rate, and simplicity of administration). In this study, we tested the hypothesis that artesunate-mefloquine (Artequin™) is as efficacious as artemether-lumefantrine (Coartem®) in treatment of uncomplicated Plasmodium falciparum malaria. The study was carried out from August 2004 through February 2005 in Kambila, Mali. Subjects with weights ≥ 10 kg and uncomplicated malaria were enrolled. Artesunate-mefloquine was given once a day for three days and artemether/lumefantrine twice a day for three days. A total of 470 (235 in each arm) patients were enrolled. The unadjusted 28-day cure rate was higher in artesunate-mefloquine arm than in the artemether-lumefantrine arm (79.7% versus 67.8%; P < 0.004). After correction for reinfection, the 28-day cure rates were similar in the two groups (96.04% versus 96.93%). Artesunate-mefloquine is well-tolerated and is as effective as artemether-lumefantrine for the treatment of P. falciparum malaria. Artesunate-mefloquine also prevented more new infections.