Background:People with HIV (PWH) have an increased risk of peripheral artery disease (PAD), but the pathogenesis is unknown. We aimed to determine the associations between markers of endothelial dysfunction and platelet activation and both PAD at baseline and de novo PAD in PWH.Methods:In total, 1012 PWH from the longitudinal Copenhagen Comorbidity in HIV-infection (COCOMO) study and 57 age-matched and sex-matched population controls were included. Plasma samples were collected at baseline and analyzed for soluble thrombomodulin, syndecan-1, and CD40 ligand (sCD40L). The ankle-brachial index was measured at baseline and two-year follow-up in PWH. Logistic and Poisson regression models were used to test associations.Results:PWH had higher concentrations of soluble thrombomodulin (P = 0.03) and syndecan-1 (P < 0.001) and lower concentration of sCD40L (P < 0.001) compared with controls. High concentration of soluble thrombomodulin, but not syndecan-1 or sCD40L, was associated with lower odds of PAD in PWH at baseline after adjustments (adjusted odds ratio: 0.50 [0.28, 0.90], P = 0.02). None of the markers were associated with de novo PAD.Conclusions:PWH had higher concentrations of soluble thrombomodulin and syndecan-1 and lower concentration of sCD40L compared with controls. Soluble thrombomodulin was associated with lower odds of PAD at baseline. Further studies are needed to elucidate the pathogenesis of PAD in people with HIV.