Pentraxin 3 (PTX3) is a novel inflammatory cytokine produced in atherosclerotic plaque. We hypothesized that this marker may be a better predictor of peripheral artery disease (PAD) than C-reactive protein (CRP) in hemodialysis (HD) patients. The ankle-brachial index (ABI) was measured in HD patients. PTX3 levels in 116 HD patients and 30 healthy blood donors were measured by ELISA. A total of 116 HD patients (age: 56.44 ± 14.08 years) were enrolled; 21 (18%) patients had PAD. PTX3 was significantly higher in PAD versus non-PAD patients (5.55 ± 2.63 vs 2.32 ± 1.29 ng/mL; p < 0.001). In a univariate analysis, ABI correlated significantly with age, blood glucose and triglycerides, and plasma PTX3 (r = -0.548, p < 0.001) and high-sensitivity (hs)CRP (r = -0.495, p < 0.001). Using ROC curve analysis for PAD, PTX3 (cut-off value 4.06 ng/mL, AUC 0.901, p < 0.0001) showed a significantly better positive predictive value than hsCRP (cut-off value 3.33 mg/L, AUC 0.640, p < 0.05). Logistic regression analysis further confirmed that PTX3 (OR = 9.755, p = 0.001) was an independent predictor of PAD. In conclusion, we demonstrated that PTX3 may be a better marker of PAD than hsCRP, and independently correlated with PAD in HD patients.