Recently, high plasma apoE levels have been shown to be related to increased cardiovascular mortality, independent of APOE genotype. Here we studied the association of plasma apoE levels with risk of stroke. Within the Leiden 85-plus Study, a prospective population-based study of 561 subjects aged 85 years, we measured plasma apoE level and determined APOE genotype at base line. The presence of stroke in the medical history and the incidence of stroke during a 5-year follow-up period were assessed by interviewing treating physicians. At base line, an increase of one standard deviation (SD) of plasma apoE level associated with a 1.47-fold higher risk of a history of stroke (P = 0.025). During follow-up, an increase of one SD of plasma apoE level associated with an increased risk of stroke (risk of stroke: 1.58, P = 0.010). This association was also observed in epsilon3epsilon3- (1.95, P = 0.002) and epsilon3epsilon4 carriers (3.01, P = 0.008), but not in epsilon2epsilon3 carriers (0.62, P = 0.440). In conclusion, in old age, except for epsilon2-allele carriers, high plasma apoE levels are associated with a higher risk of stroke, independent of APOE genotype, plasma levels of lipids, and other cardiovascular risk factors.