BACKGROUND: Peripheral Arterial Disease (PAD) is a prevalent but underdiagnosed pathology. Soluble CD146 (sCD146) was described as a marker of endothelial dysfunction and vascular congestion. OBJECTIVE: We hypothesize that sCD146 may represent a novel biomarker of PAD. Our objective was to evaluate the association between plasma sCD146 levels and the occurrence and severity of PAD. METHODS: In this case-control study, 184 Caucasian men with symptomatic PAD were compared to 163 age-matched healthy control patients. PAD diagnosis was confirmed using ankle-brachial index (ABI) and imaging. Plasma sCD146 was quantified using ELISA. Associations with clinical and biochemical parameters were analyzed through multivariable logistic regression models. RESULTS: sCD146 level was significantly reduced in PAD patients (mean [95% CI]: 288 ng/mL [269-306]) versus control patients (480 ng/mL [460-500], p < 0.0001). A 10 ng/mL decrease in sCD146 was associated with an age-adjusted odds ratio (OR) of 1.17 (95% CI 1.13-1.22) for PAD, increasing to OR 1.25 (95% CI 1.14-1.36, p < 0.0001) after adjustment for risk factors. sCD146 was not associated with PAD severity (by Fontaine stage). Notably, the association between sCD146 and HDL-C was positively correlated in controls (β = 0.220, p = 0.005), but negatively correlated in PAD patients (β = - 0.156, p = 0.041), with significant interaction (p = 0.002). Age-adjusted OR for PAD was highest in individuals with high HDL-C tertiles (OR = 1.41, 95% CI 1.22-1.63). CONCLUSION: A lower sCD146 concentration is independently associated with PAD. Additionally, an inverse relationship was observed between HDL-C and these patients. These findings suggest that sCD146 may reflect impaired endothelial homeostasis and metabolic dysregulation in PAD, indicating that it could serve as a diagnostic biomarker for the pathology. CLINICAL TRIALS REGISTRATION: NCT00377897.