BACKGROUND: Cholesterol guidelines typically prioritize primary prevention statin therapy on the basis of 10-year risk of cardiovascular disease. The advent of generic pricing may justify expansion of statin eligibility. Moreover, 10-year risk may not be the optimal approach for statin prioritization. We estimated the cost-effectiveness of expanding preventive statin eligibility and evaluated novel approaches to prioritization from a Scottish health sector perspective. METHODS: A computer simulation model predicted long-term health and cost outcomes in Scottish adults ≥40 years of age. Epidemiologic analysis was completed using the Scottish Heart Health Extended Cohort, Scottish Morbidity Records, and National Records of Scotland. A simulation cohort was constructed with data from the Scottish Health Survey 2011 and contemporary population estimates. Treatment and cost inputs were derived from published literature and health service cost data. The main outcome measure was the lifetime incremental cost-effectiveness ratio, evaluated as cost (2020 GBP) per quality-adjusted life-year (QALY) gained. Three approaches to statin prioritization were analyzed: 10-year risk scoring using the ASSIGN score, age-stratified risk thresholds to increase treatment rates in younger individuals, and absolute risk reduction (ARR)-guided therapy to increase treatment rates in individuals with elevated cholesterol levels. For each approach, 2 policies were considered: treating the same number of individuals as those with an ASSIGN score ≥20% (age-stratified risk threshold 20, ARR 20) and treating the same number of individuals as those with an ASSIGN score ≥10% (age-stratified risk threshold 10, ARR 10). RESULTS: Compared with an ASSIGN score ≥20%, reducing the risk threshold for statin initiation to 10% expanded eligibility from 804 000 (32% of adults ≥40 years of age without CVD) to 1 445 500 individuals (58%). This policy would be cost-effective (incremental cost-effectiveness ratio, £12 300/QALY [95% CI, £7690/QALY-£26 500/QALY]). Incremental to an ASSIGN score ≥20%, ARR 20 produced ≈8800 QALYs and was cost-effective (£7050/QALY [95% CI, £4560/QALY-£10 700/QALY]). Incremental to an ASSIGN score ≥10%, ARR 10 produced ≈7950 QALYs and was cost-effective (£11 700/QALY [95% CI, £9250/QALY-£16 900/QALY]). Both age-stratified risk threshold strategies were dominated (ie, more expensive and less effective than alternative treatment strategies). CONCLUSIONS: Generic pricing has rendered preventive statin therapy cost-effective for many adults. ARR-guided therapy is more effective than 10-year risk scoring and is cost-effective.