Cardiovascular disease which is associated with cardiac dysfunction, usually measured with circulating levels of B-type natriuretic peptide (BNP), has been associated with incidence and progression of diabetic peripheral neuropathy (DPN). The potential relationship of circulating physiological levels of BNP with DPN, however, has not been reported. Circulating levels of BNP were measured in 258 patients with type 2 diabetes mellitus (T2DM), and participants were divided into a DPN group ( = 61) and no DPN group ( = 197). The relationship between circulating physiological levels of BNP and DPN and other parameters was analyzed. Circulating levels of BNP were significantly elevated in T2DM patients with DPN compared to those without ( = 0.001). Circulating levels of BNP were significantly and positively associated with systolic blood pressure ( = 0.035), neutrophil-to-lymphocyte ratio ( = 0.007), creatinine ( = 0.030), vibration perception threshold values ( = 0.021), and the prevalence of diabetic foot ulceration ( = 0.039), peripheral arterial disease ( = 0.013), DPN ( = 0.032), and diabetic nephropathy ( = 0.020) and negatively with lymphocyte count ( = 0.003) and ankle-brachial index ( = 0.038), irrespective of age, sex, and body mass index. Moreover, circulating levels of BNP was an independent decisive factor for the presence of DPN after multivariate adjustment (odds ratio, 1.044; 95% confidence interval, 1.006-1.084; = 0.024). Additionally, the higher quartiles of circulating BNP were related significantly to an increased risk of DPN compared to the lowest quartile ( = 0.003). Last but most importantly, the analysis of receiver operating characteristic curves revealed that the best cutoff value for circulating levels of BNP to predict DPN was 15.18 pg/mL (sensitivity 78.7% and specificity 48.2%). These findings suggest that high circulating physiological levels of BNP may be associated with the development of DPN and may be a potential biomarker for DPN in patients with T2DM.