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Overwhelming postsplenectomy infection progresses rapidly and shows unacceptably high mortality even when treated with optimal antibiotics. Recent reports have described beneficial effects of intravenous immunoglobulin in sepsis. However, the underlying mechanisms, especially the roles of the pathogen-specific antibody fraction in intravenous immunoglobulin, remain unclear. We investigated the effects of intravenous immunoglobulin on overwhelming postsplenectomy infection and the role of pathogen-specific antibody.Prospective, controlled, and randomized animal study.University laboratory.Male C57BL/6JJcl mice.Mice underwent splenectomy or a sham operation at 8 weeks old. At 4 weeks after the operation, mice were injected intravenously with 106 colony-forming units pneumococcus. Intraperitoneal injection of 300 mg/kg IV immunoglobulins was conducted simultaneously with infection. Specific antibody–depleted IV immunoglobulin prepared using immunoprecipitation was also injected into the animals.IV immunoglobulin markedly improved splenectomized mice survival. Removal of pneumococcus-specific antibody canceled it completely. Fluorescence microscopy results indicated significantly increased phagocytosis of antibody-bound bacteria in the livers of splenectomized mice treated with intact IV immunoglobulins. Immunomodulation, including suppression of marginal zone B-cell activation, was induced by IV immunoglobulin.IV immunoglobulin showed a significantly protective effect on overwhelming postsplenectomy infection via enhancement of specific antibody–mediated phagocytosis in the liver. Specific antibody, more than immunological modulation, is crucial for effects of IV immunoglobulin on overwhelming postsplenectomy infection.