Abstract: Idiopathic Nephrotic Syndrome (INS) is a malfunction of the kidney glomerular filter that leads to proteinuria, hypoalbuminemia, edema and renal failure. The cause of proteinuria in INS is an injury to the function or structure of glomerular filtration barrier. The present study addresses the role of I/D gene polymorphism of Angiotensin Converting Enzyme (ACE), a pleiotropic molecule on the susceptibility, progression and steroid response variation of INS in South Indian population. For this study, a total of 418 subjects were recruited; 218 clinically proven cases of INS without any secondary reasons for renal problems and 200 healthy controls. Association of ACE I/D gene polymorphism with disease susceptibility, renal histological findings and response to steroid treatment was evaluated. Three significant observations were made (1) Elevated frequency of DD in patients compared to controls (37.6% vs. 17.5%, p = 0.0001) (2) Higher I allele frequency in milder form than in severe form of INS (0.52 vs. 0.29, p = 0.0001) and (3) Patients with ID genotype were 3 times more resistant to steroid treatment compared to other genotypes (z-value = 3.45, p<0.0006). ACE I/D genotypes significantly influences the susceptibility, progression and drug response variation. This information may help the clinicians to predict the course of disease and to identify individuals with better prognosis to standard steroid treatment. In order to delineate the role of different genotypes on the above aspects, its influence at the physiological level is to be studied with large sample in different ethnic groups. This is the first Indian study pertaining to primary nephrotic syndrome dealing with ACE influence on susceptibility, severity and steroid response cumulatively.