The microvascular and macrovascular effects of IL-1 receptor antagonist (IL-1ra) were examined in rat cremaster muscle A1, A2, and A3 arterioles by videomicroscopy to better define its protective effects during endotoxemia. Mean arterial pressure (MAP), arteriolar diameters, and responses to norepinephrine (NE) and acetylcholine (ACh) were examined hourly after the administration of Escherichia coli endotoxin (6 mg/kg intravenously). Animals received saline (Control) or IL-1ra (.2 mg/kg/min intravenously) beginning 1 h prior to endotoxin. Serum tumor necrosis factor-alpha (TNF-alpha) and nitrate/nitrite (NO) were determined terminally. Aortic endothelium was examined by electron microscopy (EM). All Control animals, but no IL-1ra animals, died within 6 h (p < .01).IL-1ra significantly attenuated endotoxin-induced vasoconstriction of A1 and A2 arterioles (p < .01), while MAP and NE threshold remained at baseline (p < .01 vs. Control). Serum TNF and NO were elevated following endotoxin (p < .001), but only TNF was decreased (p < .005) in animals receiving IL-1ra. Aortic endothelium was damaged in all Control animals but was spared with IL-1 antagonism. IL-1ra increases survival during endotoxic shock and attenuates production of TNF but not NO. IL-1ra maintains MAP, arteriolar diameters, reactivity of arterioles to NE and ACh, and the integrity of the aortic endothelium.