In the Amazon Basin of Peru, more than 50% of patients with uncomplicated Plasmodium falciparum malaria fail to respond to treatment with chloroquine or sulfadoxine-pyrimethamine. To assist the National Malaria Control Program in identifying an alternative first-line therapy for this region, we conducted a trial of the safety and efficacy of mefloquine (MQ) compared with mefloquine-artesunate (MQ-AS) combination therapy. Patients with uncomplicated P. falciparum infections between the ages of 5 and 50 years were randomly assigned to be treated with either MQ (15 mg/kg in a single oral dose) or MQ (15 mg/kg) plus AS (4 mg/kg/day for three days). A total of 98 patients were enrolled and followed for 28 days. None of the 47 patients who received MQ alone or the 51 patients who received MQ-AS combination therapy had recurrences of parasitemia during the 28-day follow-up period. Asexual parasite densities decreased significantly more rapidly and the proportion of patients with gametocytes was significantly lower on days 3-21 in the MQ-AS group than in patients treated with MQ alone. All patients tolerated the medication well. Based on the results of this study and with the objective of slowing the development of resistance, the Peruvian Ministry of Health has decided to revise its malaria treatment policy and recommend combination therapy with MQ-AS as the new first-line treatment of uncomplicated P. falciparum malaria in the Amazon region.