Background: Patients with sickle cell disease (SCD) are at risk of fatal sepsis with encapsulated bacteria, such as Streptococcus pneumoniae, because of the inherent autosplenectomy that occurs in SCD. This risk is thwarted with oral penicillin prophylaxis during the first 5 years of life, and with stringent vaccination against S. pneumoniae alongside routine childhood immunization. But compared with the general African American pediatric population, the rate of invasive pneumococcal disease (IPD) in patients with SCD still remains high, resulting in hospitalization and fatality., Methods: Patients with SCD who developed IPD from 2004 up to 2013 were identified using microbiology records. Descriptive analysis of presence of risk factors for IPD, type of SCD, pneumococcal vaccination and prophylaxis status, clinical presentation, microbiological data, and the outcome of IPD was performed., Results: Eight patients with SCD developed IPD (7 bacteremia and 1 respiratory tract infection). Three of the 8 isolates underwent serotype analysis (15 C in 2 and 15A in 1), none covered with the current vaccination program. One patient had fatal outcome (15A)., Conclusions: Breakthrough cases of IPD may involve nonvaccine isolates, and seem to occur after 5 years of age when oral penicillin prophylaxis has been terminated.