Objective: To assess the antiproteinuric response to multifactorial treatment based on high doses of angiotensin II receptor antagonists (ARBs) (olmesartan) in patients with non-diabetic protein uric nephropathies, according to three renin-angiotensin system (RAS) polymorphisms: insertion/deletion of the angiotensin converting enzyme (ACE) gene, the angiotensinogen gene M235T and the angiotensin II type 1 receptor (AT1R) A1166C Material and method: We studied 53 patients with non-diabetic proteinuric nephropathy with a mean progression time of 84.4+/-15 months. 41 were males (77.4%); mean age 49.7+/-3 years, body mass index 30+/-6kg/m(2). All received olmesartan (40mg/12h) associated with a mean of 2.4+/-1.6 antihypertensive drugs for a median period of 13 months (interquartile range 7-25 months). Results: Systolic blood pressure (BP) decreased from 145+/-14mmHg to 128+/-14mmHg (P<.001) and diastolic BP from 85+/-11mmHg to 79+/-7mmHg (P<.01). Pulse pressure decreased from 53.5+/-14mmHg to 48+/-12mmHg (P<.05). Proteinuria decreased from 2.74+/-1.6g/24h to 0.9+/-1g/24h (P<001), representing a mean decrease of 67.1%. According to RAS polymorphisms, antiproteinuric response was: angiotensinogen gene polymorphism: genotype TT: 76.8%; genotype MM: 67.3%; genotype MT: 65.8%, significantly higher (P<.05) for genotype TT compared to genotypes MM and MT Polymorphism of the ACE gene: genotype DD: 71.4%; genotype ID: 60.6%, genotype II: 34.8%, significantly higher (P<.05) for genotype DD compared to genotypes ID and II, and also (P<.05) for genotype ID compared to II. AT1R gene polymorphism: genotype AC: 85.2%; genotype CC: 73.7%; genotype AA: 62.7%; significantly higher for genotype AC (P<.05) compared to genotypes AA and CC. The differences between initial and final proteinuria for the follow-up period were significant (P<.01) for genotypic associations DD/AA, DD/MT, DD/MM, DD/TT and DD/AC, although the association with the highest antiproteinuric effect was DD/AC (89.9%, P<.05%). Conclusions: Administering high doses of olmesartan in patients with non-diabetic proteinuric nephropathy results in significant reductions in proteinuria. This decrease was independent of blood pressure control and other confounding factors. RAS polymorphisms may modulate the antiproteinuric response to treatment with ARBs.