Leptomeningitis due to type b Haemophilus influenzae can be produced in infant rats (up to three weeks of age) by intranasal inoculation, and in animals up to three months of age by intraperitoneal inoculation. In infant animals, the pathogenesis appears to mimic the disease in human infants. Immunologic experiments indicate that antibody directed against the type b capsule (actively or passively acquired) will protect against bacteremia (by any route of inoculation) and the subsequent development of meningitis. However, antibody directed against other surface structures of H. influenzae b (alone or with anticapsular antibody) will protect against sustained bacteremia after any route of inoculation. Evaluation of antibiotic activity against this infection in rats is unreliable due to a marked age-dependent increase in antibiotic clearance. A means of mimicking human pharmacokinetics in rats is proposed. The rat model is useful for the study of H. influenzae meningitis provided certain limitations are recognized.