A number of antiplatelet drugs, principally aspirin alone or in combination, have been evaluated in randomized trials of survivors of prior occlusive vascular disease events or of individuals at high risk because of multiple cardiovascular risk factors. In this meta-analysis we compare single and dual antiplatelet regimens to quantitate the risks of bleeding. Data from randomized trials published in English in 1988–2006 were retrieved from MEDLINE, OVID, and CARDIOSOURCE. Inclusion criteria were clinical follow-up for at least 1 month and the presence of data on bleeding complications. Information was compiled on sample size, antiplatelet agents tested, patient characteristics as well as major, minor, fatal and intracranial bleeding. Using these criteria, we identified 18 randomized trials, which included 129 314 patients. For each endpoint, relative risk (RR) and 95% confidence intervals (CI) were calculated. Dual antiplatelet therapy is associated with a significantly increased risk of major (RR 1.47, CI = 1.36–1.60) and minor bleeding events (RR 1.56, CI = 1.47–1.66) compared to single agent therapy. Although based on small numbers, there were no significant differences in fatal (RR 1.10, CI = 0.87–1.40) or intracranial (RR 1.07, CI = 0.85–1.35) bleedings although the CIs are wide to make definite assessments. Patients treated with dual antiplatelet therapy have an approximately 40–50% increase in risks of major and minor bleeding compared to those receiving single agent therapy during the duration of the scrutinized trials. The magnitude of this excess risk is not so remote from the approximately 60% increase observed in trials comparing single antiplatelet agents to placebo. This excess risk should be considered when choosing the optimal antiplatelet strategy for long-term treatment of patients with prior occlusive vascular events or those at high risk of developing occlusive vascular disease.