BACKGROUND Southeast Asia has the most resistant malaria parasites in the world, which severely limits treatment options. There is general acceptance that to combat resistance, combinations of antimalarial drugs that include an artemisinin derivative should be used, and, if possible, these should be formulated in a single tablet. METHODS We did a pilot randomised study in a tertiary referral hospital in Vietnam to compare the efficacy of 3-day regimens of dihydroartemisinin-trimethoprim-piperaquine (DHA-TP total dose 4.8/13.6/48 mg/kg, respectively) with the standard antimalarial regimen in Vietnam, artesunate-mefloquine (A3M total dose 12/25 mg/kg, respectively) in non-immune patients with uncomplicated Plasmodium falciparum malaria. 114 patients were randomised, 76 to DHA-TP and 38 to A3M. The subsequent open randomised trial at a Provincial Health Station compared DHA-TP, dihydroartemisinin-piperaquine, and A3M in 400 patients. In both studies all patients received directly observed therapy and were followed up for 56 days. The primary endpoint was reappearance of P falciparum malaria within 56 days of treatment. Analysis was by intention to treat. RESULTS The 56-day cure rate in the pilot study, adjusted for reinfections identified by PCR genotyping, was 97.4% (74/76) in the DHA-TP group and 100% (38/38) in the A3M group. In the second study, cure rates were similar in the three groups; DHA-TP 97.4% (153/157), dihydroartemisinin-piperaquine 98.7% (164/166), and A3M 98.7% (76/77). The DHA-TP and dihydroartemisinin-piperaquine regimens were well tolerated; fewer than 3% of patients had side-effects that might have been related to treatment, compared with 16% of A3M patients (p<0.001). No patients were lost to follow-up. CONCLUSIONS Dihydroartemisinin-piperaquine is an inexpensive, safe, highly efficacious fixed-dose antimalarial combination treatment that could make an important contribution to the control of multidrug-resistant falciparum malaria.