BACKGROUND: Human epididymis protein 4 (HE4) has emerged as a biomarker linked to fibrosis and cardiovascular disease. However, its prognostic relevance in peripheral artery disease (PAD) remains unclear. We therefore investigated the association of circulating HE4 with long-term outcomes in patients with PAD. METHODS: In this prospective cohort study, 291 patients with symptomatic PAD were enrolled and followed for 10 years. Serum HE4 concentrations were measured by ELISA at baseline. Primary endpoints were all-cause mortality and major adverse cardiovascular events (MACE); secondary endpoints were cardiovascular and non-cardiovascular mortality. RESULTS: During follow-up, 44.7% of patients died and 41.2% experienced MACE. In univariable models, higher HE4 levels were associated with all-cause mortality and MACE. These associations remained significant after adjustment for established cardiovascular risk factors and renal function: HR 1.35 (95% CI 1.14-1.58; p < 0.001) for all-cause mortality and HR 1.24 (95% CI 1.05-1.46; p = 0.010) for MACE per doubling of HE4. In secondary analyses, HE4 was independently associated with both cardiovascular and non-cardiovascular mortality. Addition of HE4 to established risk factors significantly improved risk discrimination and reclassification for all-cause mortality (NRI = 0.412, p < 0.001; IDI = 0.028, p = 0.004), whereas incremental prognostic value for MACE was not statistically significant. CONCLUSION: Circulating HE4 is a robust and independent predictor of long-term mortality and MACE in patients with PAD, with incremental prognostic value for mortality, primarily in terms of risk reclassification.