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A sequential combination of artesunate followed by mefloquine was evaluated prospectively in 24 patients with acute recrudescent falciparum malaria. The sequential combination was used to minimize possible side effects and to take advantage of the ability of artesunate to rapidly clear parasitemia and the prolonged effect of mefloquine to clear residual parasites. All patients had experienced one or more treatment failures with one or more courses of the following drugs (administered alone or in combination): quinine, tetracycline, mefloquine, artesunate, and sulfadoxine/pyrimethamine. Sequential treatment with artesunate (600 mg over five days) followed by mefloquine (750 mg and 500 mg six hours apart) cured all 24 patients. Each patient was followed for 28 days and 10 were observed for at least 35 days without clinical or parasitologic evidence of recrudescence. Fever and parasite clearance times after treatment with the sequential combination were 32.8 ± 19.3 hr (mean ± SD) and 40.0 ± 16.2 hr, respectively. Susceptibility testing of selected parasite isolates indicated that all of the isolates tested were resistant to one or more antimalarial drugs. These results suggest that sequential treatment with artesunate followed by mefloquine is effective and well-tolerated in patients with recrudescent falciparum malaria.