The penetration of cefamandole and ampicillin into the cerebrospinal fluid of rabbits with and without pneumococcal meningitis was evaluated. In normal animals, a mean maximum concentration of 0.22 +/- 0.13 microgram of cefamandole per ml was measured in the spinal fluid after a dose of 150 mg/kg given intramuscularly; with 25 and 50 mg/kg doses, no antibiotic was detected in the cerebrospinal fluid. With ampicillin, in intramuscular doses of 200 and 300 mg/kg, the mean maximum concentrations encountered in the cerebrospinal fluid were 1.59 +/- 0.4 and 1.47 +/- 0.44 microgram/ml, respectively. Penetration of cefamandole, and to a lesser extent ampicillin, was increased after 24 h of experimental meningitis. With cefamandole, the concentration of drug in the cerebrospinal fluid exceeded the usual inhibitory concentration for Haemophilus influenzae only with the 150 mg/kg dose. After 48 h of meningitis, there was a trend toward higher levels of antibiotic in the cerebrospinal fluid, but the difference between animals infected 24 versus 48 h was not statistically significant. In animals with meningitis, serum concentrations after 150 mg of cefamandole per kg and both ampicillin doses studied were 32 to 38% lower than the serum levels achieved in normal rabbits after identical doses of antibiotic.