The renin-angiotensin system (RAS) is a hormonal signaling mechanism widely known as a blood pressure regulation system. The classic pathway begins with the release of renin (REN), an aspartyl-protease that cleaves angiotensinogen (AGT) to produce angiotensin I (AngI), which is later hydrolyzed by the angiotensin I-converting enzyme (ACE) to produce angiotensin II (AngII); this octapeptide exerts its functions through its specific receptors, angiotensin II receptor type 1 and type 2 (AGTR1 and AGTR2 respectively). 1 Most of the physiological effects such as blood vessel constriction have been attributed to the AGTR1 signaling pathway. In recent years, however, research papers have described mitogenic and angiogenic activities as well, activities that are also mediated through AGTR1. 2,3 Since angiogenesis and proliferative processes are related to the development, progression and metastasis of cancer, it is reasonable to believe that RAS may have a role in cancer. 4 When ACE insertion-deletion (indel) polymorphism was examined as a cancer risk marker, it was associated with gastric, endometrial, prostate and breast cancer. [5][6][7][8][9][10][11][12][13] However, three different AGTR polymorphisms presented contradictory results when studied for breast cancer. [13][14][15] For every biological system each component contributes to the overall effect; therefore, to explain any phenomenon, a more integrated approach is needed. To date, no study has included more than two RAS genes. With this in mind, in the present work we explored the association between breast cancer and some of the major polymorphisms of the four Abstract Recent information has revealed new roles in the angiogenic processes linked to the rennin-angiotensin system. To date few studies have been done on the association between RAS genes and cancer and the majority focus mainly on angiotensin I-converting enzyme (ACE). For breast cancer there are three reports that include the angiotensin II receptor, subtype 1 (AGTR1), only one for angiotensinogen (AGT) and none for renin gene (REN). In the present study we investigate whether REN (BglI), AGT (M235T), ACE (A245T, Indel), and AGTR1 (A1166C) are associated with breast cancer. Polymorphisms were analysed by PCR and RFPLs or sequence specific assay in three groups: breast cancer, benign breast disease (BBD) and general population. REN polymorphism shows that homozygous for A allele have an increased risk for BBD. Differences in M235T genotype frequencies were significant with less heterozygous in breast cancer. With different risk values ACE indel was associated with BBD and breast cancer. Association of AGTR1 was observed only in the breast cancer group, where C allele carriers present a reduced risk. Results of this work supports previous observations on the possible involvement of this system in breast cancer but it also suggests a role in benign disease.