Induction of pneumonia in C57Bl/6 mice by intranasal inoculation with 106 cfu of Streptococcus pneumoniae resulted in sustained expression of interleukin (IL)-6 mRNA in lungs and increases in lung and plasma IL-6 concentrations. In IL-6-deficient (IL-6−/−) mice, pneumonia was associated with higher lung levels of the proinflammatory cytokines tumor necrosis factor-α, IL-1β, and interferon-γ and of the antiinflammatory cytokine IL-10 than in wild type (IL-6+/+) mice (all P < .05). Also, the plasma concentrations of soluble tumor necrosis factor receptors were higher in IL-6−/− mice (P < .05), while the acute-phase protein response was strongly attenuated (P < .01). Lungs harvested from IL-6−/− mice 40 h after inoculation contained more S. pneumoniae colonies (P < .05). IL-6−/− mice died significantly earlier from pneumococcal pneumonia than did IL-6+/+ mice (P < .05). During pneumococcal pneumonia, IL-6 down-regulates the activation of the cytokine network in the lung and contributes to host defense.