Hrom February 1974 through May 1975, 58 isolates of ampicillin-resistant Hemophilus influenzae from patients were submitted to the Center for Disease Control from 23 states and the District of Columbia. The epidemiologic characteristics of these widely scattered cases were strikingly similar to those of cases previously reported from individual communities or institutions. Because of the nationwide distribution of resistant isolates and the adverse consequences of ineffective therapy, the use of chloramphenicol is recommended for the initial management of systemic illness definitely or probably due to H. influenzae type b.