The difficulties in treating drug-resistant falciparum malaria in Thailand are compounded by the necessity of giving antimalarials over long periods of time. The resultant decrease in patient compliance not only lowers cure rates but also predisposes to the further spread of drug resistance. We compared the efficacy of two sequential treatment regimens given over two and three days in 111 patients with acute uncomplicated falciparum malaria. Sixty-seven patients received two 400-mg doses of artesunate (total dose = 800 mg) followed by two doses of mefloquine (750 mg given immediately and 500 mg 12 hr later; total dose = 1,250 mg) in Group I. Forty-four patients (Group II) received four 200-mg doses of artesunate (total dose = 800 mg) given 12 hr apart followed by a mefloquine regimen similar to that for Group I. All patients were admitted to hospital in Bangkok for 28 days to preclude reinfection. Ninety-six patients completed the study. Cure rates for the two groups were 84% (49 of 58) for Group I and 100% (38 of 38) for Group II. The mean parasite clearance time and fever clearance time were significantly shorter in Group II (P < 0.02). There were no serious adverse reactions. All nine of the treatment failures in Group I were of the RI type. The results indicate that the sequential treatment with artesunate followed by mefloquine given over three days is effective and well-tolerated in patients with acute, uncomplicated falciparum malaria and suitable as an alternative treatment for multidrug-resistant falciparum malaria.