There is an international trend towards recommending medication to prevent cardiovascular disease (CVD) in individuals at increasingly lower cardiovascular risk. We assessed the cost-effectiveness of a population approach with a polypill including a statin (simvastatin 20 mg) and three antihypertensive agents (amlodipine 2.5 mg, losartan 25 mg and hydrochlorothiazide 12.5 mg) and periodic risk assessment with different risk thresholds. We developed a microsimulation model for lifetime predictions of CVD events, diabetes, and death in 259 146 asymptomatic UK Biobank participants aged 40-69 years. We assessed incremental costs and quality-adjusted life-years (QALYs) for polypill scenarios with the same combination of agents and doses but differing for starting age, and periodic risk assessment with 10-year CVD risk thresholds of 10% and 20%. Restrictive risk assessment, in which statins and antihypertensives were prescribed when risk exceeded 20%, was the optimal strategy gaining 123 QALYs (95% credible interval (CI) -173 to 387) per 10 000 individuals at an extra cost of £1.45 million (95% CI 0.89 to 1.94) as compared with current practice. Although less restrictive risk assessment and polypill scenarios prevented more CVD events and attained larger survival gains, these benefits were offset by the additional costs and disutility of daily medication use. Lowering the risk threshold for prescription of statins to 10% was economically unattractive, costing £40 000 per QALY gained. Starting the polypill from age 60 onwards became the most cost-effective scenario when annual drug prices were reduced below £240. All polypill scenarios would save costs at prices below £50. Periodic risk assessment using lower risk thresholds is unlikely to be cost-effective. The polypill would become cost-effective if drug prices were reduced.