Procedures for evaluating the efficacy of chemotherapeutic agents in an infant rat model of Haemophilus influenzae meningitis were developed. The results of efficacy studies with ampicillin, chloramphenicol, cefamandole, cefoxitin, and SQ 13,426 were compared to activity in vitro. While most of the drugs tested were very active against the two strains of H. influenzae used in vitro, this activity was not in all cases translated into efficacy in vivo. Pharmacokinetic studies using ampicillin or chloramphenicol demonstrated the presence of each antibiotic at the foci of infection in concentrations found to be bactericidal in vitro.