We examined the association between the ε4 allele of the apolipoprotein E gene and severity of peripheral neuropathy in 234 patients with type 2 diabetes mellitus (T2DM). Based on the Neuropathy Disability Score (NDS), patients were divided into group A (NDS =6: mild or no neuropathy) and group B (NDS >6: severe neuropathy). In each group, patients were further divided into ε4 carriers and non-ε4 carriers. In multivariate analysis, a more than 5-fold increased risk of severe neuropathy was associated with ε4 carrier status (adjusted odds ratio [aOR]: 5.26, 95% confidence interval [CI]: 2.24-12.31, P =.0001). The other significant risk factors for severe neuropathy included male gender (aOR: 2.08, 95% CI: 1.05-4.14, P =.036), diabetes duration (aOR: 1.05, 95% CI: 1.00-1.09, P =.039), and hemoglobin A1c (aOR: 1.32, 95% CI: 1.05-1.66, P =.020). In conclusion, the ε4 carrier status appears to be associated with severe peripheral neuropathy in T2DM.