Sublethal doses of E. coli endotoxin were shown to cause direct slowing of blood flow in the isolated perfused rat liver. Concentrations as low as SO ng per ml elicited this vasoconstrictive response. The decrease in flow after the initial lipopolysaccharide injection was immediate and lasted from. 5 to 15 minutes before recovering to baseline values. Succeeding injections of the same concentration, however, had little or no circulatory effects, and this tachyphylaxis persisted through 5 hours of perfusion. The replacement of the perfusate with fresh whole blood after several hours partially restored the ability of the hepatic vasculature to respond to the lipopolysaccharide. However, the presence of plasma or formed blood elements was not essential to the response, as brisk decreases occurred after endotoxin when a modified Ringer's solution was the sole perfusate. Catecholamines or serotonin did not appear to be key mediators in the primary vascular effect of endotoxin as phentolamine and methysergide administration did not appreciably modify the response. On the other hand, hydrocortisone when given in large doses with the endotoxin or in smaller doses 15 to 45 minutes prior to the lipopolysaccharide completely blocked vasoconstriction. The isolated preparation seems to be an excellent model for the study of direct circulatory effects of various substances in the liver.