A combination of quinine and tetracycline is a standard regimen for the treatment of acute uncomplicated falciparum malaria. Frequent administration due to its short half-life (6-8 hours), long duration of drug administration (7 days), and side effects of quinine (cinchonism e.g. tinnitus, nausea, vomiting, palpitation, etc) may cause the patient not to complete the whole course of treatment and recrudescence ensues. A previous study of artesunate followed by mefloquine given once daily for 3 days gave a greater than 95% cure rate. The objective of this study is to determine the efficacy and tolerability of a combination of artesunate and mefloquine (ASM group) compared with a combination of quinine and tetracycline (QT group) in 120 uncomplicated falciparum malaria cases. In the ASM group, 60 patients received 200 mg artesunate and 312.5 mg mefloquine 12-hourly for 2 days (a total of 800 mg artesunate and 1,250 mg mefloquine). Another 60 cases received 600 mg quinine sulfate 8-hourly and 250 mg tetracycline 6-hourly for 7 days. Both groups were admitted to the Somdejprachaotaksinmaharaj Hospital, Tak Province until either parasite negative or until there were no clinical signs or symptoms of malaria. 108 cases completed the 28-day follow-up. The results showed a similar 28-day cure rate (96.2% in the ASM group vs 94.6% in the QT group), however side effects such as tinnitus (25.8% vs 83.3%), vomiting (51.6% vs 80.6%), and palpitation (32.3% vs 80.6%) were less common in the ASM group. In addition, parasite clearance time (PCT) and the time taken to produce clinical improvement were significantly shorter in the ASM group (p < 0.05). In conclusion, a combination of artesunate and mefloquine may be an alternative regimen for treatment of uncomplicated falciparum malaria especially for outpatients in remote areas. In addition, this will shorten the duration of patients’ hospital stay.