Cefamandole and ampicillin were compared in the therapy of experimental Haemophilus influenzae meningitis in rabbits. Three dosages of each drug were administered as a continuous intravenous infusion for 8 hr to 24 infected animals. Samples of serum and cerebrospinal fluid (CSF) were obtained at 0, 4, and 8 hr for determination of antibiotic concentrations and bacterial titers in CSF. Serum levels of cefamandole were higher, but CSF concentrations of both antibiotics were similar. With the 60-mg/kg per hr dose, the mean serum level was 106 +/- 61 mug/ml for cefamandole and 58 +/- 32 mug/ml for ampicillin (P less than 0.05). With this dosage the mean level in CSF was 7.3 +/- 8.4 mug/ml for cefamandole and 9.5 +/- 5.4 mug/ml for ampicillin (P = 0.26). The percentage penetration ([concentration in CSF/concentration in serum] X 100%) was higher for ampicillin (mean, 18.8% +/- 8.9%) than for cefamandole (mean, 5.6% +/- 3.8%) with all dosages tested (P less than 0.001). The rate of bacterial killing in vivo during therapy was similar with both drugs. The efficacy of cefamandole and ampicillin given intramuscularly for five days (250 mg every 8 hr) was examined in 42 rabbits. Twelve of 14 untreated control rabbits died within 24-72 hr of inoculation. In contrast, 11 of 14 rabbits treated with cafamandole and 10 of 14 rabbits treated with ampicillin were cured of their infections. Cefamandole compared favorably with ampicillin in the therapy of experimental H. influenzae meningitis.