We studied prospectively 801 Thai patients admitted to the Bangkok Hospital for Tropical Diseases with acute, symptomatic Plasmodium vivax malaria to determine the optimum duration of treatment with oral artesunate and the safety, tolerability, and effectiveness of a high dose of primaquine in prevention of relapse. Patients were randomly assigned to one of four treatment groups: 1) a five-day course of artesunate (Group A5); 2) a seven-day course of artesunate (Group A7); 3) a five-day course of artesunate plus a 14-day course of high-dose primaquine (0.6 mg/kg, maximum dose = 30 mg) (Group A5 + P); and 4) a seven-day course of artesunate plus a 14-day course of high-dose primaquine (Group A7 + P). During 28 days of observation, P. vivax reappeared in the blood of 50% of those who received artesunate alone (Groups A5 and A7), compared with none of those who received primaquine (Groups A5 + P and A7 + P; P < 0.0001). Adverse effects were confined to the 13 patients with a deficiency for glucose-6-phosphate dehydrogenase; high-dose primaquine (0.6 mg/kg of base a day) had to be stopped in four (31%) patients because of a significant decrease in the hematocrit. The combination of five days of artesunate and 14 days of primaquine is a highly effective and generally well-tolerated treatment regimen for vivax malaria in Thailand.