Mice deficient in CD18, which lack all four CD11 integrins, have leukocytosis and increased susceptibility to bacterial infection. To determine the effect of deficiencies in LFA-1 (CD11a/CD18) or Mac-1 (CD11b/CD18) on host defense against systemic bacterial infection, knockout mice were inoculated ip with Streptococcus pneumoniae. Increased mortality occurred in both LFA-1−/−(15 of 17 vs 13 of 35 in wild type (WT), p< 0.01) and Mac-1−/−(17 of 34 vs 6 of 25, p< 0.01) mice. All deaths in LFA-1−/− mice occurred after 72 h, whereas most deaths in Mac-1−/− mice occurred within 24–48 h. At 24 h, 21 of 27 Mac-1−/− mice were bacteremic, vs 15 of 25 WT (p= 0.05); no difference was observed between LFA-1−/− and WT. Increased bacteria were recovered from Mac-1−/− spleens at 2 h (p= 0.03) and 6 h (p= 0.002) and from livers (p= 0.001) by 6 h. No difference was observed at 2 h in LFA-1−/− mice, but by 6 h increased bacteria were recovered from spleens (p= 0.008) and livers (p= 0.04). Baseline and peak leukocyte counts were similar between Mac-1−/− and WT, but elevated in LFA-1−/−. At 8 h, peritoneal neutrophils were increased in Mac-1−/−, but not significantly different in LFA-1−/−. Histopathologically, at 24 h Mac-1−/− animals had bacteremia and lymphoid depletion, consistent with sepsis. LFA-1−/− mice had increased incidence of otitis media and meningitis/encephalitis vs WT at 72 and 96 h. Both Mac-1 and LFA-1 play important but distinct roles in host defense to S. pneumoniae.