Background: Understanding how sex influences the pathophysiology of cardiovascular and renal disease may enhance precision medicine approaches that account for sex specific biologic differences in these diseases. Nevertheless, characterization of preclinical models often fail to account for the role of sex on important pathophysiologic mechanisms. The renin-angiotensin-aldosterone system (RAAS) plays a central role in the development and progression of cardiovascular and renal disease. In addition to the classic RAAS pathway, an alternative RAAS pathway produces angiotensins (e.g. Ang [1-7]) that can counteract classical RAAS hormones such as Angiotensin (Ang) II. We hypothesized that RAAS profiling in a high-salt fed Dahl-S rat model would reveal significant sex differences in both classic and alternative RAAS pathways. Methods/Results: Ten week-old male and female Dahl-S rats were fed either 0.2% salt normal chow (SS-NC), or 8% high-salt diet (SS-HS) for eight weeks (n=6-8/group). Equilibrium RAAS profiling via LC-MS/MS was performed in lithium heparin plasma samples. In response to high-salt diet, both male and female SS-HS rats had significant (p<0.05) reductions vs. their respective SS-NC controls in plasma aldosterone (-93% in male SS-HS, -97% in female SS-HS), Ang II (-71% in male SS-HS, -41% in female SS-HS), Ang IV (-79% in male SS-HS, -54% in female SS-HS) as well as calculated plasma renin activity (-67% in male SS-HS, -42% in female SS-HS), although the magnitude of reduction was generally greater in males vs. females. Alternatively, only male SS-HS rats had significant (p<0.05 vs. SS-NC) reductions in plasma Ang I (-63%), Ang III (-66%), as well RAAS metabolites of the alternative RAS axis, Ang [1-5] (-58%) and Ang [1-7] (-70%) vs. SS-NC. Comparing female vs. male SS-HS rats, females had significantly (p<0.01 vs. male) increased levels of angiotensins of the classic RAS pathway, such as Ang I (113%), Ang II (104%), Ang III (150%) and Ang IV (265%) after high-salt diet. Conclusion: High-salt diet induces significant sex-dependent differences in both classic and alternative RAAS pathways of Dahl-S rats and may provide important insight into the sex-dependent differences of cardiovascular and renal injury seen in this model.