Overwhelming infections caused by encapsulated bacteria are an important cause of morbidity and death in children with sickle cell anemia. The most important contributing factors to this increased susceptibility to infections are an opsonophagocytic defect due to an abnormality of the alternate pathway of complement activation, a state of functional hyposplenia, and a lack of specific circulating antibodies as a developmental phenomenon. If the inordinately high, early mortality rate associated with sickle cell anemia is to be prevented, early diagnosis of affected infants is crucial. Prophylactic therapy with penicillin has been advocated in recognition of the fact that a majority of the causative organisms are sensitive to penicillin. However, no controlled studies have proved the effectiveness of such therapy. Immunization with broadly polyvalent vaccines against Streptococcus pneumoniae, Haemophilus influenzae type b, and Neisseria meningitidis may ultimately represent the most effective way to reduce the incidence of catastrophic infections.