Macrophages release proinflammatory cytokines in response to infection that play a critical role in the pathophysiology of septic shock. We propose that targeting cytokine-neutralizing antibodies using albumin microspheres to macrophages will be more beneficial than the soluble form in reducing mortality related to peritonitis. In this study, we compared the distribution pattern of microspheres in infected and noninfected animals, evaluated the amount of microsphere taken up by peritoneal macrophages in vitro, and compared the efficacy of soluble and microsphere forms of cytokine-neutralizing antibodies in preventing lethality caused by Escherichia coli-induced peritonitis. The results indicate that twice the amount of microspheres accumulates near the site of infection (the peritoneal cavity), and 70% of the microspheres exposed to peritoneal macrophages were phagocytosed in 1 h. Treatment with the microsphere form of cytokine-neutralizing antibodies was more efficacious than using the soluble form in preventing lethality induced by E. coli. Immediate treatment was more efficacious than delayed treatment in the absence of gentamicin, whereas immediate and delayed treatment were equally efficacious in the presence of gentamicin. The combination of microspheres containing neutralizing antibodies to tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) protected 100% of the animals, whereas either one alone protected only 60%-90% of the animals from lethality caused by E. coli-induced peritonitis. In conclusion, the microsphere form of neutralizing antibodies to TNF-alpha IL-1beta may be an effective therapeutic agent in the treatment of septic shock caused by peritonitis.