Background Although clopidogrel reduces the incidence of atherothrombotic events, its use is associated with an increased risk of major bleeding. Cerebral microbleeds ( CMB s) are indicative of subclinical microangiopathy in the brain and may prelude symptomatic intracerebral hemorrhage. We examined the association between use of clopidogrel and CMB s in persons without a history of stroke. Methods and Results We performed a cross‐sectional analysis using data from the Rotterdam Study, a prospective population‐based cohort of persons aged 45 years and older. Among 4408 stroke‐free individuals who underwent brain magnetic resonance imaging for the detection of CMB s, we identified 121 ever‐users and 4287 never‐users of clopidogrel before magnetic resonance imaging. We used multiple logistic regression to analyze the association between clopidogrel and CMB s with adjustment for age, sex, cardiovascular risk factors, and common cardiovascular medication. Users of clopidogrel had a higher prevalence of CMB s (odd ratio 1.55, 95% CI 1.01 to 2.37) than nonusers and more often had a high number (>4) of CMB s (odds ratio 3.19, 95% CI 1.52 to 6.72). Clopidogrel use was associated with a significantly higher prevalence of deep or infratentorial CMB s (odd ratio 1.90, 95% CI 1.05 to 3.45). Among clopidogrel users, we were unable to demonstrate differences in the prevalence of CMB s by indication of prescription, history of coronary heart disease, or common genetic variants in CYP 2C19 . Conclusions In stroke‐free individuals, clopidogrel use was associated with a higher prevalence and higher number of CMB s. Whether this association is causal requires confirmation in prospective studies, especially given the small number of participants taking clopidogrel and the possibility of residual confounding in this study.