Invasive disease due to Haemophilus influenzae type b (Hib) resistant to chloramphenicol and ampicillin is rare in the United States. Review of the literature reveals that all previously reported cases occurred in children with meningitis. These children were treated initially with ampicillin and chloramphenicol and had complicated courses characterized by delayed sterilization of the cerebrospinal fluid. The present report describes an infant who developed meningitis due to ampicillin- and chloramphenicol-resistant Hib. The patient received cefotaxime from the onset of therapy and had an uncomplicated course. The presence of Hib strains resistant to chloramphenicol and ampicillin should be considered in patients with meningitis due to Hib who respond poorly to treatment with these two drugs. Furthermore, the in vitro susceptibility of all Hib isolates to chloramphenicol (as well as to other antimicrobial agents) should be evaluated routinely. If the incidence of such resistant organisms increases, a change will be warranted in the commonly recommended combination of ampicillin and chloramphenicol as empiric therapy for bacterial meningitis in pediatric patients.