Mice genetically deficient in the gene encoding for intercellular adhesion molecule-1 (ICAM-1) production were compared with wild-type mice after injection with Haemophilus influenzae type b (Hib) or Streptococcus pneumoniae. The incidence of Hib bacteremia was greater in the ICAM-1-deficient mice than wild-type mice (P = .007), but mortality was greater for wild-type mice at 24 h (P = .03). In contrast, the incidence of S. pneumoniae bacteremia was equivalent but mortality was greater in ICAM-1-deficient mice at 24 h (P = .0003). More ICAM-1-deficient mice had cerebrospinal fluid cultures (CSF) positive for Hib (P = .04), whereas all animals at sacrifice had CSF cultures positive for S. pneumoniae. CSF white blood cell counts and histology of the meninges and cochlea were no different between groups for either organism. ICAM-1 deficiency may be protective early in Hib infection but has a detrimental effect in S. pneumoniae infection.