OBJECTIVES: The aim of the present study was to estimate the cost-effectiveness of the polypill in the primary prevention of cardiovascular disease. DESIGN: A health economic modeling study. SETTING: Primary health care in the Netherlands. PARTICIPANTS: Simulated individuals from the general Dutch population, aged 45-75 years of age. INTERVENTIONS: Opportunistic screening followed by prescription of the polypill to eligible individuals. Eligibility was defined as having a minimum 10-year risk of cardiovascular death as assessed with the SCORE function of alternatively 5%, 7.5%, or 10%. Different versions of the polypill were considered, depending on composition: 1) the Indian polycap, with three different types of blood pressure lowering drugs, a statin, and aspirin; 2) as 1) but without aspirin; 3) as 2) but with a double statin dose. In addition, a scenario of (targeted) separate antihypertensive and/or statin medication was simulated. PRIMARY OUTCOME MEASURES: Cases of acute myocardial infarction or stroke prevented, QALYs gained, and the costs per QALY gained. All interventions were compared with usual care. RESULTS: All scenarios were cost-effective with an incremental cost-effectiveness ratio between €7,900-12,300 per QALY compared with usual care. Most health gains were achieved with the polypill without aspirin and containing a double dose of statins. With a 10-year risk of 7.5% as threshold, this pill would prevent approximately 3.5% of all cardiovascular events. CONCLUSIONS: Opportunistic screening based on global cardiovascular risk assessment followed by polypill prescription to those with increased risk offers a cost-effective strategy. Most health gain is achieved by the polypill without aspirin and a double statin dose.