Two groups of rabbits with experimental meningitis induced by direct intracisternal inoculation of Streptococcus pneumoniae cells were studied. One group was rendered profoundly leukopenic by nitrogen mustard, and the other had normal leukocyte counts. The two groups had comparable bacterial growth rates (mean generation time, 60 versus 67 min) and ultimate bacterial populations in the cerebrospinal fluid (CSF) (mean log10 CFU, 9.1 versus 8.7); therefore leukocytes did not effectively slow or limit the growth of pneumococci in the CSF in vivo. Increased CSF protein, decreased CSF glucose, and increased CSF lactate levels were similar in both groups, suggesting that leukocytes are not essential for these changes to occur. Quantitative blood cultures revealed identical levels of pneumococcal bacteremia until 13 to 14 h after the initiation of infection, when the leukopenic rabbits showed a larger number of pneumococci in the blood, ultimately exceeding the number reached in nonleukopenic rabbits by 100-fold. Leukocytes therefore limit the extent of pneumococcal bacteremia after infection of the CSF despite their lack of effect on the course or the CSF manifestations of experimental meningitis.