BACKGROUND: Streptococcus pneumoniae is the most common causative organism in community-acquired pneumonia. Pneumococci that try to invade the lower airways are recognized by innate immune cells through pattern recognition receptors, including Toll-like receptors 2, 4, and 9. Interleukin 1 (IL-1) receptor-associated kinase (IRAK)-M is a proximal inhibitor of Toll-like receptor signaling. METHODS: To determine the role of IRAK-M in host defense during pneumococcal pneumonia, IRAK-M- deficient and wild-type mice were intranasally infected with S. pneumoniae. RESULTS: IRAK-M-deficient mice demonstrated a reduced lethality after infection with S. pneumoniae via the airways. Whereas bacterial burdens were similar in IRAK-M-deficient and wild-type mice early (3 hours) after infection, from 24 hours onward the number of pneumococci recovered from lungs and distant body sites were 10-100-fold lower in the former mouse strain. The diminished bacterial growth and dissemination in IRAK-M-deficient mice were preceded by an increased early influx of neutrophils into lung tissue and elevated pulmonary levels of IL-1beta and CXCL1. IRAK-M deficiency did not influence bacterial growth after intravenous administration of S. pneumoniae. CONCLUSIONS: These data suggest that IRAK-M impairs host defense during pneumococcal pneumonia at the primary site of infection at least in part by inhibiting the early immune response.