Background:DN is a major microvascular complication of T2DM. Genetic factors, particularly polymorphisms in the RAGE gene, have been implicated in DN susceptibility. Objective: This study aimed to evaluate the association of the -429T/C RAGE gene polymorphism with DN in T2DM patients from South India.Materials and Methods:150 subjects, including HC, T2DM patients without nephropathy, and T2DM patients with DN, were enrolled. Genotyping of the -429T/C polymorphism was performed using PCR-RFLP with BsmFI enzyme.Results:The frequency of the TT genotype decreased progressively from 78% in HC to 58% in T2DM and 42% in DN. Conversely, the CC genotype increased from 8% in HC to 22% in T2DM and 28% in DN. The C allele frequency also rose from 0.15 in HC to 0.43 in DN. These differences were statistically significant. Discussion andConclusion:The -429T/C RAGE gene polymorphism is significantly associated with DN in South Indian T2DM patients. The presence of the C allele appears to increase susceptibility to DN, whereas the TT genotype may confer a protective effect.