The combination of artesunate and mefloquine is currently one of the most effective treatments against multidrug-resistant Plasmodium falciparum malaria. To improve patient compliance to such a combination, the two agents have been combined in a prepacked single blister. Patients were instructed to simultaneously co-administer the drugs once a day for three days. In the present randomized, double-blind, parallel group, comparative, single center study in Thailand, this concept was investigated in 204 adults and children with acute, uncomplicated P. falciparum malaria. Patients were randomized into two treatment groups and received once a day over a three-day period the following: Group A received artesunate, 4-5 mg/kg/day, and mefloquine, total dose = 25 mg/kg, approximately 8.5 mg/kg/day, simultaneously. Group B received artesunate, 4-5 mg/kg/day, and mefloquine, total dose = 25 mg/kg, sequentially (i.e., no mefloquine dose on the first day, 15 mg/kg on the second day, and 10 mg/kg on the third day). Both treatment groups showed no relevant differences in baseline demographic and clinical characteristics. Intent-to-treat analysis revealed a cure rate at day 28 (primary endpoint) of 100% in group A and 99% in group B (difference not significant). The secondary endpoints of mean time to fever clearance (group A = 34 hours, group B = 31 hours) and mean time to parasite clearance (group A = 44 hours group B = 48 hours) were similar between groups (both differences not significant). Tolerability was good in both treatment groups, with no difference in the overall incidence of adverse events. There was a low incidence of nausea/vomiting (4.9% in both groups) and central nervous system side effects (4.9% in group A versus 8.8% in group B). These were comparable between groups and generally of a mild nature. The three-day combination of artesunate and mefloquine (Artequin, Mepha, Ltd., Aesch, Switzerland) with the introduction of mefloquine on day 1 offers a practical dosing regimen that is highly effective and well tolerated in patients of different ages with uncomplicated P. falciparum malaria. It is likely that the prepacked blister approach translates clinically into a better patient compliance, thereby contributing to limit the development of drug resistance.