A diabetic foot ulcer is considered as the most serious diabetes complication. This study was intended to estimate the association of (C667T) SNP (rs180113) in the methylenetetrahydrofolate reductase (MTHFR) enzyme with the DSF predisposition, and the role of some non-genetic risk factors in the diabetic Sudanese population. A cross-sectional case-control study was conducted, 55 were diabetic septic foot (DSF) patients represent the case group, and 75 diabetic patients (DM) without septic complication as control. The (C667T) (rs180113) Polymorphism was detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) using Hinf I enzyme. Diabetic septic foot (DSF0 with retinopathy showed a highly significant difference compared to DM with retinopathy (p-value = 0.006), with three times increased risk of DSF (OR = 3.527). Concerning the genotype analysis, the homozygous wild type genotype CC showed high frequency among cases and control with the following percentage (96.7%, 100%) respectively. No significant association between the mutant genotype and DSF predisposition. The results of this study indicate that MTHFR (C667T) (rs180113) polymorphism is not associated with the increased risk of diabetic septic foot among Sudanese diabetic patients, and neuropathy, retinopathy might be strong pathological cases lead to diabetic septic foot development.