We aimed to assess whether the effectiveness of statins in the prevention of myocardial infarction, stroke and total mortality is influenced by apolipoprotein E (apoE) genotype in an elderly population. We used data from the Rotterdam Study, a prospective population-based cohort study in the Netherlands which started in 1990 and included 7983 subjects aged 55 years and older. Subjects who were treated with cholesterol lowering drugs at baseline or with a serum total cholesterol > or = 6.5 mmol/l at baseline were included. We compared the incidence of myocardial infarction, stroke and total mortality in subjects who received > or = 2 years of statin treatment with that in subjects who had been treated for less than 2 years, and in untreated subjects, using a Cox proportional hazard model with cumulative statin use defined as time-dependent covariates. The adjusted relative risk of all-cause mortality was 0.79 [95% confidence interval (CI) 0.51-1.22] and of myocardial infarction and stroke 0.50 (95% CI 0.28-0.91) for subjects treated with statins for > or = 2 years compared to untreated subjects. The adjusted relative risks for subjects with the epsilon4 allele were 0.91 (95% CI 0.45-1.84) for all-cause mortality and 0.63 (95% CI 0.23-1.78) for myocardial infarction and stroke. In subjects without the epsilon4 allele, adjusted relative risks were 0.71 (95% CI 0.41-1.24) for all-cause mortality and 0.46 (95% CI 0.22-0.95) for myocardial infarction and stroke. We found a protective effect of statins on the risk of myocardial infarction and stroke that was independent of apoE genotype. The protective effect of statins on total mortality was not statistically significant, but did not seem to differ between subjects with different apoE genotypes.