AIMS: To estimate the potential effectiveness of different "high-risk" and "population" approaches to the primary prevention of cardiovascular disease (CVD) in middle-aged British men, after correction for regression dilution bias. METHODS AND RESULTS: We used a combination of cohort and randomised controlled trial evidence to estimate the effectiveness of high-risk strategies, based on the identification of high-risk factors or high absolute risk, and strategies based on population-wide reductions in cholesterol and blood pressure. High-risk strategies were potentially effective but would need to be used widely to have a substantial effect on CVD in the population. Aggressive pharmacological treatment (using statins, beta-blockers, ACE-inhibitors and aspirin) in individuals with a 10-year Framingham event risk of >or=30% (6% of population) would have reduced major CVD by at most 11%. This figure increased to 34% at a >or=20% treatment threshold (26% of population). In contrast, modest downwards shifts in the population distributions of serum total cholesterol and systolic blood pressure led to marked expected reductions in major CVD. Taking regression dilution bias into account, 10% reductions in long-term mean blood cholesterol and blood pressure could have reduced major CVD by 45%. CONCLUSIONS: If high-risk strategies are to have a major impact on CVD in the population, they need to be more widely used than previously envisaged. Population-wide reduction of major risk factors is needed if CVD is to be substantially reduced.