One hundred fifty-one patients with acute uncomplicated falciparum malaria were enrolled in a randomized, open-label study of oral artemether given alone for five or seven days or a sequential treatment of oral artemether followed by mefloquine. Forty patients received oral artemether, 100 mg initially, then 50 mg every 12 hr for a total dose of 500 mg over a five-day period: Group I. Fifty-eight patients received oral artemether, 100 mg initially, then 50 mg every 12 hr for a total dose of 750 mg over a seven-day period: Group II. Fifty-three patients received oral artemether, 200 mg every 8 hr for a total dose of 600 mg, followed 8 hr later with mefloquine (1,250 mg divided into two doses given 6 hr apart: Group III. All patients were admitted to the hospital for 28 days to exclude reinfection and 131 patients remained through the 28-day follow-up. Only two, nine, and nine patients in Groups I, II, and III, respectively, left the hospital prior to study completion for reasons unrelated to their treatment. Cure rates for the three groups were 74% (28 of 38) for Group I, 98% (48 of 49) for Group II, and 98% (43 of 44) for Group III. Mean fever and parasite clearance times were not significantly different (32.8, 27.5, and 31.4 hr for fever clearance times and 40.2, 40.6, and 36.7 hr for parasite clearance times of Groups I, II, and III, respectively) nor were any adverse effects seen. In vitro drug susceptibility testing of admission and recrudescent parasite isolates was conducted for 10 patients. These data showed no decreased response to artemether or dihydroartemisinin in recrudescent isolates when compared with admission isolates. The results of this study suggest that sequential treatment for two days with oral artemether (600 mg) followed by mefloquine (1,250 mg) is effective and well-tolerated in patients with acute uncomplicated falciparum malaria and may be an alternative treatment for multidrug-resistant falciparum malaria, particularly useful for treating patients in rural areas where the period of admission to the hospital should be as short as possible. A seven-day regimen of artemether alone (750 mg) is also very effective, yet requires prolonged administration of drug after malaria symptoms disappear.