The survival of interleukin (IL)-13-deficient (IL-13 −/−) mice was significantly lower compared with that of wild-type mice during bloodstream infection with Streptococcus pneumoniae. Serum immunoglobulin M (IgM) levels and complement C3 (C3) mRNA expression in bone marrow-derived dendritic cells were also significantly lower in IL-13 −/− mice compared with wild-type mice, which partially explains their impaired resistance. The results indicate an important role for IL-13 in regulating IgM and C3 production and provide insight into humoral innate immunity against systemic pneumococcal infections. This is the first report demonstrating reduced host resistance associated with IL-13 deficiency during pneumococcal bacteremia.