Aims The aim of this study was to determine whether clopidogrel plus aspirin provides greater protection against major cardiovascular events than aspirin alone in patients with peripheral arterial disease (PAD). Methods and results This is a post hoc analysis of the 3096 patients with symptomatic (2838) or asymptomatic (258) PAD from the CHARISMA trial. The rate of cardiovascular death, myocardial infarction (MI), or stroke (primary endpoint) was higher in patients with PAD than in those without PAD: 8.2% vs. 6.8% hazard ratio (HR), 1.25; 95% CI 1.08, 1.44; P = 0.002. Among the patients with PAD, the primary endpoint occurred in 7.6% in the clopidogrel plus aspirin group and 8.9% in the placebo plus aspirin group (HR, 0.85; 95% CI, 0.66–1.08; P = 0.18). In these patients, the rate of MI was lower in the dual antiplatelet arm than the aspirin alone arm: 2.3% vs. 3.7% (HR, 0.63; 95% CI, 0.42–0.96; P = 0.029), as was the rate of hospitalization for ischaemic events: 16.5% vs. 20.1% (HR, 0.81; 95% CI, 0.68–0.95; P = 0.011). The rates of severe, fatal, or moderate bleeding did not differ between the groups, whereas minor bleeding was increased with clopidogrel: 34.4% vs. 20.8% (odds ratio, 1.99; 95% CI, 1.69–2.34; P < 0.001). Conclusion Dual therapy provided some benefit over aspirin alone in PAD patients for the rate of MI and the rate of hospitalization for ischaemic events, at the cost of an increase in minor bleeding.