The association between venous thromboembolism (VTE) and antibodies anti-Protein C (PC)/Protein S (PS) is still uncertain. We performed a case-control study to determine the risk of VTE related to the presence of these auto-antibodies considered independently of the presence of lupus anticoagulant (LAC) or anti-cardiolipin antibodies (ACA). One hundred thirty-five patients with idiopathic VTE and 164 healthy subjects were enrolled. Anti-PC and anti-PS antibodies (both IgG and IgM) were assessed using commercially available ELISA kits. Among cases there was a higher prevalence of elevated anti-PC IgM antibodies than in controls (OR 2.44, 95%CI 1.00-5.94). The presence of anti-PC IgG and anti-PS IgG and IgM antibodies was also higher in cases than in controls, but the difference was not statistically significant. Only five patients had both anti-PC or anti-PS antibodies and LAC or ACA. We performed a stepwise multivariate logistic regression analysis showing that anti-PC IgM>958 percentile was a significant predictor of VTE after adjustment for LAC or ACA (OR 2.52, 95%CI 1.01-6.24)). Larger prospective studies are needed to confirm this finding.