We performed a cross-sectional case-control study among 295 subjects with dementia and 406 control subjects drawn from participants of the Rotterdam Study, a population-based cohort study among subjects aged 55 years or over, and from participants of the Rotterdam Stroke Databank, a hospital-based stroke registry, to evaluate the association of the factor V Leiden mutation and activated protein C (APC) response with dementia and its subtypes. The risk of dementia was 2.11-fold increased among carriers of factor V Leiden mutation relative to subjects lacking factor V Leiden mutation (95% confidence interval, CI, 0.93-4.77). The increased risks of vascular dementia and of Alzheimer's disease were 4.28 (95% CI 1.26-14.5) and 2.15 (95% CI 0.82-5.63), respectively. No association was found for APC response. We showed a nonsignificant twofold increased risk of dementia among subjects with factor V Leiden. The association appeared to be stronger for vascular dementia.