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Sixty-three patients with severe falciparum malaria were randomly administered one of the two regimens of a sequential combination of artesunate suppository followed by an oral mefloquine tablet. Thirty-two patients received artesunate suppositories (200 mg/capsule) given rectally at 0, 4, 8, 12, 24, 36, 48, and 60 hr (total = 1,600 mg: Group I). Thirty-one patients received the same artesunate suppositories given rectally at 0, 12, 24, 36, 48, and 60 hr (total = 1,200 mg: Group II). Both regimens were followed by two doses of oral mefloquine, 750 mg given at 72 hr and 500 mg at 84 hr. Patient baseline characteristics were comparable in the two groups. All patients were admitted for 28 days to the Bangkok Hospital for Tropical Diseases to assess efficacy, tolerability, and delayed neuropsychiatric effects. The mean [SD] parasite clearance time was significantly shorter in Group I than Group II (47.3 [12.4] hr versus 55.3 [17.4] hr; P = 0.05) and the rate of parasite reduction was significantly faster in Group I (P = 0.05, by log-rank test). Mean [SD] fever clearance times were similar in the two Groups (71.1 [41.2] hr and 76.9 [47.9] hr, respectively). Twenty-two patients with unrousable coma on admission (median Glasgow Coma Score = 9) regained consciousness after 1–4 days. No deaths occurred. Sixty of sixty-three patients were parasitologically and clinically cured within 3–4 days of treatment. Three patients (5%) with deteriorating conditions required rescue treatment (one patient in Group I was administered intravenous artesunate, and two patients in Group II required two extra doses of suppository). No patients had major adverse drug effects. The cure rates at 28 days of follow-up in Group I were 96% (26 of 27 patients) and 89% (24 of 27 patients) in Group II. Artesunate suppository followed by mefloquine was well tolerated and effective. In severe malaria, the sequential treatment is a suitable alternative treatment to parenteral drugs. Further studies in a larger number of patients under field conditions are required.