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Cerebral microbleeds (CMBs) are associated with increased risk of stroke and poor cognition. Vascular risk factors and medications used for stroke prevention may increase the risk of CMB. We examined the prevalence of CMB and the association of these risk factors with CMB, postulating that risk factors for cerebral amyloid angiopathy would be associated with lobar CMB and markers of hypertensive vasculopathy with deep CMB.We include 1965 Framingham Original and Offspring participants (age, 66.5±11.0 years; 54% women) and evaluated the age- and sex-specific prevalence of CMB. We related various vascular and genetic (apolipoprotein E [APOE]) risk factors and medication use to the presence of CMB overall and stratified by brain location (deep, lobar, or mixed).CMBs were observed in 8.8% of participants, being mostly lobar (63%). CMB prevalence increased with age (P<0.0001) and was higher in men (P<0.001). Hypertension increased risk of any CMB, and in deep and mixed locations (P<0.05), and low total cholesterol and APOE ε4 increased risk of lobar CMB (P<0.05). Statin use increased risk of lobar and mixed location CMB (P<0.05). The latter association was not affected by adjustment for cholesterol levels or concomitant medication use.We observed the expected association of hypertension with deep CMB and low cholesterol and APOE ε4 with lobar CMB. In addition, statin use was independently associated with CMB risk. This potential adverse effect of statin use needs to be examined in other cohorts.