Activation of the Renin-Angiotensin-Aldosterone-System (RAAS) is proposed to play a role in the development of insulin resistance and type II diabetes. Angiotensin II (AngII) is a principal effector molecule that binds AT1 receptors (AT1R) in various tissues. Recent data shows that activated endothelial cells secrete protein disulfide isomerase (PDI), a multifunctional protein that has been shown to be critical to the initiation and regulation of thrombus formation. However, the effects of RAAS on PDI regulation are unknown. We hypothesized that RAAS activation would lead to increased PDI levels thus contributing to inflammation. First, we studied the in vitro effects of AngII on EA.hy926 human endothelial cells and measured PDI activity. Our results show that AngII increased PDI activity; an event that was blocked by preincubation with 0.5 M losartan, an AT1R antagonist (ARB) (P<0.05, n=6). We then studied the in vivo effects of exogenous AngII infusion in Sprague–Dawley rats under the following conditions: (1) control; (2) AngII infused; (3) AngII + ARB. In these rats, AngII infusion led to significant increases in plasma PDI levels that were partially prevented by ARB treatment (P<0.05, n>5). We then studied the obese Otsuka Long Evans Tokushima Fatty (OLETF) (n = 6/group) rats, a model of naturally increased AngII and RAAS mediated insulin resistance and hypertension. OLETF and their lean strain controls were randomly assigned to the following groups: (1) untreated Long Evans Tokushima Otsuka (lean, control); (2) untreated OLETF; (3) OLETF + ARB. Our results show that OLETF rats had increased insulin resistance and significantly greater circulating PDI activity than control rats (P<0.05) that was likewise blocked by ARB treatment (P<0.05). To assess the relevance to humans of these findings we measured circulating PDI levels in patients with type 2 diabetes. In our cohort, PDI activity was significantly greater in patients with type 2 diabetes than non diabetics (P<0.001, n=134). Our data suggest that RAAS activation represents a novel mechanism for PDI secretion. Thus we posit that PDI may contribute to the deleterious effects of RAAS-mediated vascular disease.