Abstract Background Despite substantial improvement in secondary preventive therapy, the burden of recurrent cardiovascular (CV) events remains high. Peripheral artery disease (PAD), is a potential marker of increased residual ischemic risk in acute coronary syndrome (ACS) patients suggesting greater net clinical benefit from intensified individualized therapy. Purpose We aimed to assess the prevalence and cardiovascular (CV) outcomes of peripheral arterial disease (PAD) in 4'787 patients with acute coronary syndromes (ACS) in the Swiss prospective multicenter SPUM study. Methods PAD was defined according to international guidelines. The composite primary endpoint was major adverse cardiac and cerebrovascular events (MACCE), i.e., stroke, myocardial infarction (MI) and death at 1 year. Adjusted Cox proportional hazards regression models were used to estimate the risk associated with PAD and outcomes. Results Out of 4'787 ACS patients, 285 patients (6.0%) had PAD. These patients were older (70.1±10.6 vs 63.3±12.4, p<0.001), presented all traditional CV risk factors (all p<0.001) and were more likely to have a complex history of CV disease, such as previous MI (24.3% vs 11.4%, p<0.001), prior percutaneous (32.3% vs 13.8%, p<0.001) or surgical (12.6% vs 3.5%, p<0.001) coronary revascularization. PAD-patients presented also higher levels of inflammatory biomarkers, such as hs-CRP, and GRACE 2.0 score (all p<0.001). At 1 year, patients with PAD had a higher rate of MACCE compared to those presenting without PAD. Rates of the individual components of the primary endpoint and CV-death were all significantly higher in patients with PAD (all p<0.001), except for a numerical increase in MI (5.3% vs 3.3%, p=0.060). This enhanced risk persisted after adjustment for differences in baseline characteristics, with a 53% (Adj. HR 1.53, CI95% 1.14–2.08, p=0.005) increase in MACCE. In spite of high-intensity anti-thrombotic therapy, PAD patients presented the same rate (Adj. HR 1.03, CI95% 0.68–1.54, p=0.901) of major bleeding events at 1 year. Conclusions Among a real-world cohort of ACS patients, the coexistence of PAD, a very-high CV risk phenotype, is associated with significantly increased rates of MACCE, but no difference in major bleeding events. These observations might help clinicians to further stratify this very-high risk population and to identify patients who may derive the greatest benefit from more intense secondary prevention therapies. Funding Acknowledgement Type of funding sources: None.