BACKGROUND AND OBJECTIVES: Previous studies have indicated that febrile children with sickle cell disease (SCD) had a 3% to 5% risk of being bacteremic due to compromised immune function. The introduction of routine penicillin prophylaxis and conjugate vaccines may have lowered the risk of bacteremia. Our goals were to determine the rate of bacteremia among children with SCD per febrile episode and to estimate the safety of outpatient management among these febrile SCD patients. METHODS: This 18-year retrospective cohort study included febrile SCD patients who presented to Boston Children’s Hospital between 1993 and 2010. RESULTS: A total of 1118 febrile episodes were evaluated. Nine blood specimens had growth of a pathogen in culture (0.8%; 95% confidence interval: 0.3%–1.3%). Of the 466 febrile patients initially managed as outpatients, 3 were bacteremic (0.6%). All 3 received intravenous ceftriaxone at the initial outpatient visit and returned when contacted after growth of bacteria was detected in the blood culture. Upon return to the hospital, none were “ill appearing,” required supportive care, or were admitted to an ICU. CONCLUSIONS: Our rate of bacteremia among febrile children with SCD is much lower than previous estimates, and there was no associated morbidity or mortality among the patients managed as outpatients. A well-appearing febrile child with SCD may be managed as an outpatient after blood is obtained for bacterial culture and parenteral antibiotics are administered, provided there are no other reasons for admission and the patient is able to return promptly for worsening condition or for growth of a pathogen from their blood culture.