In this nested case-control study of 57 patients who had participated in a clinical trial of primaquine for radical cure of acute P vivax malaria, exposure to low levels of cytochrome P450 2D6 activity determined by genotype or measured by dextromethorphan metabolism phenotype was associated with a significantly increased likelihood of relapse of malaria in the year after directly observed high-dose primaquine therapy. This evidence concerns the gene CYP2D6 and malaria.