Hypothesis: Flutamide, a testosterone receptor antagonist, produces various beneficial effects in male rats following hemorrhagic shock, possibly as a result of a direct vasodilating effect on large and small vessels in the rat. Design, Interventions, and Main Outcome Measures: The aorta and the small intestine were isolated from normal male and female Sprague-Dawley rats. Isolated aortic rings were placed in the organ bath and constricted by 2 × 10-7M norepinephrine bitartrate (Sigma, St Louis, Mo). Flutamide-induced and testosterone-induced vascular relaxation dose-response curves were then determined. The dose-response curves of flutamide were also determined in the small blood vessels of the isolated small intestine under conditions of constant flow following preconstriction induced by 5 × 10-6M norepinephrine bitartrate. The effects of prior incubation with testosterone (8 × 10-5M) and sex differences on flutamide-induced vascular relaxation were also examined in aortic rings and in the small intestine. Moreover, flutamide-induced relaxation in endothelium-denuded aortic rings and in aortic rings from animals subjected to trauma and hemorrhagic shock was examined. Results: Flutamide induced significant relaxation in aortic rings and small intestinal blood vessels in healthy males. The flutamide-induced relaxation in vessels from normal males was partially attenuated by prior incubation with the male sex steroid testosterone, and was significantly lower in females. Flutamide-induced vascular relaxation in the aorta was partially attenuated by endothelium removal, but it was not significantly affected by trauma and hemorrhagic shock in male rats. Conclusions: Flutamide has a direct vasodilating effect on large and small vessels in rats, which involves sex-dependent mechanisms. Thus, the beneficial effects of flutamide on cardiovascular responses in males following trauma and hemorrhagic shock may be due to the direct vascular relaxation induced by this agent.