Cost-effectiveness analysis was done to evaluate the potential health and economic effects of a genetic screening program to identify individuals at risk for rheumatic fever (RF). The current RF prevention strategy was compared with a new, primary prevention strategy involving early genetic testing and intensive prophylaxis to prevent a first attack among individuals at high risk for RF. When analysis of a hypothetical 2000 birth cohort was done from a societal perspective, the prevention strategy involving genetic screening and prophylaxis for high-risk persons reduced the number of RF cases and increased life span at an estimated discounted cost of $7900 per quality-adjusted life-year gained. Genetic screening became the preferred (least expensive) strategy if the test specificity was >/=98%, the annual cost of prophylaxis was <$550, or the annual cost of caring for an individual with severe rheumatic heart disease increased to >$32,000. When used with available antibiotic prophylaxis, genetic testing has the potential to provide a cost-effective strategy for the primary prevention of RF and its sequelae.