Introduction: T2DM is a major metabolic disorder often complicated by DN, a leading cause of ESRD. RAGE is occupied in the pathogenesis of DN through its interaction with AGEs, promoting oxidative stress and soreness. Genetic polymorphisms in the RAGE gene, particularly in the promoter region, may influence susceptibility to diabetic complications. This study evaluated the association of the-429T/C polymorphism of the RAGE gene with T2DM and DN in the South Indian population. Objective: The current research was undertaken to investigate the connotation of the-429T/C polymorphism of the RAGE gene with Type 2 Diabetes Mellitus (DM) and its progression to diabetic nephropathy (DN) in the South Indian population. Methods: This Case-control study was directed on 150 subjects, including 100 T2DM patients (50 with DN and 50 without DN) and 50 HC. DNA was removed from peripheral blood, and the-429T/C polymorphism was analyzed by PCR-RFLP using the BsmFI restriction enzyme. Genotypic and allelic distributions were associated across groups using the Chi-square test. Results: Genotypic distribution among HC, T2DM, and DN groups was as follows: TT genotype—78%, 58%, and 42%; TC genotype—7%, 10%, and 15%; and CC genotype—8%, 22%, and 28%, respectively. The T allele frequencies were 0.85, 0.68, and 0.57, while C allele frequencies were 0.15, 0.32, and 0.43, across the three groups. A decreasing trend in the protective TT genotype and a corresponding increase in the risk-associated CC genotype were observed from controls to T2DM and subsequently to DN, indicating a strong genetic influence of the C allele in disease progression. Conclusion: The-429T/C RAGE gene polymorphism is significantly allied with susceptibility to DN in South Indian patients with T2DM. The TT genotype appears protective, while the C allele may increase the risk of nephropathy progression. © 2025 Elsevier B.V., All rights reserved.