Introduction: Children with sickle cell disease (SCD) remain at higher risk for invasive infection with Streptococcus pneumoniae compared to the general pediatric population. Penicillin prophylaxis, pneumococcal conjugate (PCV), and polysaccharide vaccines (PPSV) have reduced the incidence of pneumococcal disease. Methods: A single institution cohort of children with SCD aged <19 years was reviewed over the 14-year period after PCV13 licensure (January 2010 – December 2023) to identify and characterize the clinical features and outcomes of S. pneumoniae bacteremia, including serotypes and antibiotic susceptibility. Results: The cohort included 4,356 children with SCD (24,076 person-years). Thirty-eight pneumococcal bacteremia cases were identified (32 HbSS, 5 HbSC, 1 HbSβ ⁺-thalassemia), 21 (55%) in children age ≥5 years. The median time to culture positivity was 10.6 hours (range 3.4–20.2) from collection. Meningitis occurred in 4 (11%) and acute chest syndrome in 13 (34%). Serotype information was available for 36 (95%) isolates, which included 16 (44%) PPSV23 serotypes and 1 (2.6%) PCV13 serotype (serotype 3). Penicillin nonsusceptibility occurred in 12/31 (39%) at meningitis and 1/31 (3%) at non-meningitis breakpoints. Three (8%) deaths occurred (serotypes 12F, 23B, and 15B), all in children age ≥5 years, who had discontinued prophylactic penicillin. Long-term sequelae occurred in 5 (14%) surviving children, including hearing loss, limb amputation, motor and neurocognitive defects. Conclusion: Pneumococcal bacteremia continues to occur in children with SCD, with a risk of rapid progression to severe disease. Pneumococcal prevention strategies and urgent empiric treatment for fever remain important for children and adolescents of all ages with SCD.