Background Clopidogrel combined with aspirin is routinely prescribed after coronary artery stenting, in patients with acute coronary syndromes, and recently to prevent stroke in patients with acute minor ischemic stroke and TIA. Subdural hematomas are an important complication of antithrombotic treatment, but the risk associated with clopidogrel plus aspirin has not been previously defined. Purpose To quantify the risk of subdural hematoma associated with dual antiplatelet therapy with clopidogrel plus aspirin. Methods Randomized clinical trials comparing clopidogrel plus aspirin with aspirin alone were identified by searching the Cochrane Central Register of Controlled Trials from 1990 to 2014, and restricted to those with more than 7 days of treatment. Two reviewers independently extracted data about subdural hematomas. Results Of 24 randomized trials testing clopidogrel added to aspirin, results for subdural hematoma were available for 11 trials, of which eight did not identify any subdural hematomas. The three trials reporting subdural hematomas were double-blind and included patients with recent lacunar stroke, acute coronary syndromes or atrial fibrillation with a total of 23,136 patients (mean age 66 years) and reported 39 subdural hematomas during a mean follow-up 2·1 years per patient. Clopidogrel plus aspirin was associated with a significantly increased risk of subdural hematoma compared with aspirin alone (risk ratio 2·0, 95% CI 1·0, 3·8; P = 0·04; fixed effects model; I² for heterogeneity of 0%, P = 0·51). The average absolute incidence of subdural hematoma averaged 1·1 (95%CI 0·7,1·6) per 1000 patient – years among those assigned clopidogrel plus aspirin in 11 randomized trials. Conclusions The absolute rate of subdural hematoma during dual antiplatelet therapy is low, averaging 1·1 per 1000 patient-years. Chronic treatment with clopidogrel plus aspirin significantly increases the risk of subdural hematoma compared with aspirin alone.