This cross-sectional study tested the hypothesis that APOE genotype is a risk factor for diabetic neuropathy severity. A model with age, duration of diabetes, and APOE genotype was found to predict (p = 0.0083) severity on the Neuropathy Impairment Score in the Lower Limbs (NISLL). Considering genotype alone, patients with APOE 3/4 and 4/4 genotypes had 3 more NISLL points than patients with other genotypes. This impact on severity is equivalent to having 15 extra years of age or diabetes duration.