Pneumococcal sepsis and/or meningitis are major causes of morbidity and mortality in young children with sickle cell disease. Abnormal complement activity, poor splenic function and a lack of type-specific pneumococcal antibody are responsible for the severity and frequency of these infections. A program consisting of early institution of antibiotic therapy for febrile episodes, antimicrobial prophylaxis, and administration of pneumococcal vaccine may be effective in reducing the incidence of pneumococcal disease. Specific guidelines for infection prevention are presented. Other infections that are more frequent or more severe in children with sickle cell disease (e.g., Salmonella, Haemophilus and mycoplasma infections) are also discussed.