Phagocytes of the reticuloendothelial system are important in clearing systemic infection; however, the role of the reticuloendothelial system in the response to localized infection is not well documented. The major goals of this study were to investigate the roles of phagocytes in the reticuloendothelial system in terms of bacterial clearance and inflammatory modulation in sepsis caused by pseudomonas pneumonia. Macrophages in liver and spleen were depleted by administering clodronate-encapsulated liposomes intravenously 36h prior to the instillation of P. aeruginosa into the lungs of anesthetized rabbits. Blood samples were analyzed for bacteria and cytokine concentrations. Lung injury was assessed by the bidirectional flux of albumin and by wet to dry weight ratios. Blood pressure and cardiac outputs decreased more rapidly and bacteremia occurred earlier in the clodronate-treated rabbits compared with the non-depleted rabbits. Plasma TNF- (1.08±0.54 vs. 0.08±0.02ng/ml) and IL-8 (6.8±1.5 vs. 0.0±0.0ng/ml) were higher in the depleted rabbits. The concentration of IL-10 in liver of the macrophage-depleted rabbits was significantly lower than in normal rabbits at 5h. Treatment of macrophage depleted rabbits with intravenous IL-10 reduced plasma proinflammatory cytokine concentrations, and reduced the decline in blood pressure and cardiac output. These results show that macrophages in the reticuloendothelial system have critical roles in controlling systemic bacteremia and reducing systemic inflammation, thereby limiting the systemic effects of a severe pulmonary bacterial infection.