Diabetic nephropathy (T2DN) is a major micro vascular complication associated with type-2 diabetes (T2DM). Abnormally active Renin Angiotensin System pathway is shown to influence the development of T2DN and the inter-individual variation with respect to ACE levels, a key enzyme in this pathway partly dependent on the genetic variants of ACE; suggests patient’s genotype may influence the progression and severity of diabetes and its complications. The current study explores the impact of synonymous variant of ACE rs4343 in the propensity, age at onset and disease duration of T2DM and T2DN in south Indians. This case-control study includes blood samples from 100 T2DN, 100 T2DM and 100 healthy controls (HC). Genomic DNA was extracted, PCR-RFLP based genotyping of ACE rs4343 polymorphism was performed and appropriate statistical analysis was done. Elevated frequency of G allele and GG genotype in T2DN group in comparison with T2DM patients and HC was noted (p<0.05). Among the T2DN vs. T2DM patients with ≤ 45 yrs of age GG genotype showed 3.4 fold increased risk towards development of nephropathy (p<0.05). Further, GG imparted a 3 fold elevated risk among T2DN patients having ≤ 7 years of diabetic duration before the onset of nephropathy than the patient group with ≥ 7 years of diabetic duration (p<0.05). Multiple Logistic Regression analysis revealed BMI, W/H ratio, AAOM, DODM, and GG genotype as an independent risk factors for the development of T2DN. To our knowledge this is the first study of rs4343 polymorphism in the perspective of age at onset and progression of T2DN presenting a significant association of mutant genotype with both the aspects in south Indian population. To realize these findings studies with large sample are warranted in various ethnic group.