High mobility group box 1 (HMGB1), a nuclear protein, once released to the extracellular space, participates in pathological pain including chemotherapy-induced peripheral neuropathy (CIPN) and diabetic peripheral neuropathy (DPN). Endothelial thrombomodulin (TM) causes thrombin-dependent degradation of HMGB1, and TMα, a soluble form of TM, prevents CIPN in mice, an effect reversed by thrombin inhibitors. Intriguingly, repeated treatment with anticoagulants aggravates CIPN itself in mice. Thus, we examined the effect of TMα and/or thrombin on DPN in mice, and retrospectively analyzed the association between the use of anticoagulants and DPN in diabetic patients. In reptin receptor-deficient db/db mice, known as a model for type 2 diabetes, repeated treatment with TMα prevented the development of DPN, an effect reversed by argatroban, a thrombin inhibitor. Of 1036 diabetic patients hospitalized in Kansai Medical University Hospital in 2018, 615 who met inclusion criteria were enrolled in this study. Multivariate logistic regression analysis after propensity score matching showed that prescription of anticoagulants was significantly associated with the development of DPN. Thus, our data suggest that the TM/thrombin system functions to reduce DPN, and its inhibition by anticoagulants is a risk for DPN.