Objective To investigate the clinical relationship between serum Omentin-1 levels and diabetic peripheral neuropathy (DPN) in patients with type 2 diabetes mellitus (T2DM). Methods A total of 122 patients hospitalized from March 2017 to September 2017 were enrolled in this study, among which were 67 patients with T2DM (Control group) and 55 patients with DPN (DPN group). Clinical characteristics were recorded. Logistic regression model andlinear logistic analysis were performed to screen the risk factors of DPN. ROC curve was established to analyze the diagnostic efficacy of Omentin-1and its association with DPN severity. Results Levels of Omentin-1 were downregulated significantly in the DPN group compared with control group, and was negatively correlated with homeostatic model assessment for insulin resistance index (HOMA-IR) (r = -0.375, P = 0.000) and glycated hemoglobin (HbAlc) (r = -0.445, P = 0.001). Multivariate logistic regression analysis results revealed that HbAlc [O^R = 4.003, (95% CI: 1.016, 10.776)] and HOMA-IR [O^R = 4.595, (95% CI: 1.709, 12.324) ] were independent risk factors for DPN, while Omentin-1 was a protective factor of DPN [O^R = 0.257, (95% CI: 0.112, 0.589) ]. ROC curve suggested that the area under the curve for Omentin-1 detecting DPN was 0.713 (95% CI: 0.622, 0.804), and the optimal cut-off value was 18.8 ng/ml with sensitivity of 69.7% and specificity of 71.8%. Omentin-1 was negatively correlated with TCSS scores (r = -0.606, P = 0.000). Conclusions Omentin-1 is an independent protective factor of DPN.