The only available treatment that can eliminate the latent hypnozoite reservoir of vivax malaria is a 14 d course of primaquine (PQ). A potential problem with long-course chemotherapy is the issue of compliance after clinical symptoms have subsided. The present study, carried out at an Afghan refugee camp in Pakistan, between June 2000 and August 2001, compared 14 d treatment in supervised and unsupervised groups in which compliance was monitored by comparison of relapse rates. Clinical cases recruited by passive case detection were randomised by family to placebo, supervised, or unsupervised groups, and treated with chloroquine (25 mg/kg) over 3 days to eliminate erythrocytic stages. Individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency were excluded from the trial. Cases allocated to supervision were given directly observed treatment (0.25 mg PQ/kg body weight) once per day for 14 days. Cases allocated to the unsupervised group were provided with 14 PQ doses upon enrollment and strongly advised to complete the course. A total of 595 cases were enrolled. After 9 months of follow up PQ proved equally protective against further episodes of P. vivax in supervised (odds ratio 0.35, 95% CI 0.21-0.57) and unsupervised (odds ratio 0.37, 95% CI 0.23-0.59) groups as compared to placebo. All age groups on supervised or unsupervised treatment showed a similar degree of protection even though the risk of relapse decreased with age. The study showed that a presumed problem of poor compliance may be overcome with simple health messages even when the majority of individuals are illiterate and without formal education. Unsupervised treatment with 14-day PQ when combined with simple instruction can avert a significant amount of the morbidity associated with relapse in populations where G6PD deficiency is either absent or readily diagnosable.