Angiotensin II (Ang II) AT₁ receptor blockade reduces inflammation in hypertension. To determine whether Ang II AT1 receptor blockers (ARBs) influence the innate immune inflammatory response in normotensive rats, we studied rat plasma and spleen after a three-day i.p. pretreatment with the ARB candesartan, followed by a single i.p. administration of 50µg/kg of the bacterial endotoxin lipopolysaccharide (LPS). Peripheral administration of LPS to rodents produced a generalized inflammatory response with increased release of TNF-, IL-1 and IL-6 to the circulation. Candesartan pretreatment reduced the LPS-induced release of TNF-, IL-1, and IL-6 into the circulation. The red pulp of rat spleen expressed large numbers of AT₁ receptors and the LPS receptors TLR4 and CD14. Candesartan administration significantly blocked AT₁ receptors. The ARB reduced the LPS-induced up-regulation of the following: CD14 gene expression; expression of TNF- and IL-6 mRNA and protein; expression of IL-1 and IB- mRNA; COX-2 mRNA and protein expression and PGE₂ concentration; iNOS gene and protein expression and iNOS activity; Nox2 gene expression and 8-isoprostane levels. In addition candesartan reduced the CD14 protein expression in both saline and LPS-treated rats. Our results suggest that AT₁ receptors are essential for the development of the full innate immune response to bacterial endotoxin. The ARB decreased the general peripheral inflammatory reaction to LPS and partially decreased the inflammatory response in the spleen. An unrestricted innate immune response to the bacterial endotoxin may have deleterious effects for the organism and may lead to development of chronic inflammatory disease. We postulate that ARBs may have therapeutic effects on inflammatory conditions.