Hyposplenism, secondary to splenectomy or disease state, predisposes the host to overwhelming infection with certain bacteria, such as S. pneumoniae. Recognition of the hyposplenic state and preventive measures, including patient education and vaccination, appear to reduce the rate of this highly fatal infection. In addition to considering chemoprophylaxis, a clinician should promptly evaluate or empirically treat all febrile episodes in hyposplenic patients.