We assessed the efficacy of mefloquine monotherapy and mefloquine-artesunate (MQ-AS) combination therapy for the treatment of Plasmodium falciparum malaria at four sites in the Bolivian Amazon region. Patients with uncomplicated P. falciparum infections between 5 and 60 years of age 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 daily for 3 days). A total of 143 patients were enrolled and followed for 28 days. None of the 73 patients who received MQ alone or the 70 patients who received MQ-AS combination therapy had recurrences of parasitaemia during the 28-day follow-up period. Asexual parasite densities fell significantly more rapidly and the proportion of patients with gametocytes was significantly lower on days 7-28 in patients treated with MQ-AS than in those treated with MQ alone. All patients tolerated the medications well. After this study, the Bolivian Ministry of Public Health changed its treatment policy for uncomplicated P. falciparum malaria in the Amazon region to combination therapy with MQ-AS to slow or prevent the development of resistance.