Invasive pneumococcal disease (IPD) in children with sickle cell disease (SCD) can be devastating. We sought to assess the impact of IPD in children with SCD since licensure of the pneumococcal conjugate vaccines (PCVs). We found 11 cases of IPD giving an incidence of 417 per 100,000 person-years, much higher than that reported in children without SCD. Although all isolates were sensitive to penicillin, 89% of isolates were nonvaccine serotypes. Further study is needed to characterize the incidence of and risk factors for the development of IPD in SCD in the PCV era to help drive better prevention strategies.