The role of IL-1 in susceptibility to Streptococcus pneumoniae infection was studied in mice deficient in genes of the IL-1 family [i.e. IL-1α-/-, IL-1β-/-, IL-1α/ β-/- and IL-1R antagonist (IL-1Ra)-/- mice] following intra-nasal inoculation. Intra-nasal inoculation of S. pneumoniae of IL-1β-/- and IL-1α/ β-/- mice displayed significantly lower survival rates and higher nasopharyngeal and lung bacterial load as compared with control, IL-1α-/- and IL-1Ra-/- mice. Treatment of IL-1β-/- mice with rIL-1β significantly improved their survival. A significant increase in blood neutrophils was found in control, IL-1α-/- and IL-1Ra-/- but not in IL-1β-/- and IL-1α/β-/- mice. Local infiltrates of neutrophils and relatively preserved organ architecture were observed in the lungs of IL-1α-/- and control mice. However, S. pneumoniae-infected IL-1β-/-, IL-1α/β-/- and IL-1Ra-/- mice demonstrated diffuse pneumonia and tissue damage. Altogether, all three isoforms contribute to protection against S. pneumoniae; our results point to differential role of IL-1α and IL-1β in the pathogenesis and control of S. pneumoniae infection and suggest that IL-1β has a major role in resistance to primary pneumococcal infection while the role of IL-1α is less important.