Sickle cell disease (SCD) is the most common inherited hematologic disorder in the United States. Patients with SCD are at increased risk of invasive pneumococcal disease and are reliant on both early penicillin prophylaxis and antipneumococcal vaccination for prevention of infection. Although studies examining vaccine response have demonstrated a drop-off of titer response after 3 years, an optimal vaccination regimen has not been identi-fied. Our study sought to assess the immunogenicity of our center's pneumococcal vaccination strategy, which included Prevnar (PCV-7) (before the introduction of PCV-13) followed by Pneumovax (PPV-23) given routinely at 2 and 5 years of age and then every 5 years thereafter. Our goal was to assess vaccine response in a population of patients with SCD who had received vaccines according to this regimen using multiplex bead analysis. Our study demonstrated a significant percentage of persons with SCD do not maintain a sufficient vaccination response to PPV-23 for 5 years. Our study revealed that only 36% of patients had protective levels of antipneumococcal antibody titers at an average of 37 months after vaccination. Most alarmingly, within the group of patients with subtherapeutic titers, 64% demonstrated vaccine response to <25% of the tested serotypes. These findings were significantly associated with duration of time since last vaccine administration, but the mean age of lack of response was below the 3-year window where vaccine response was previously reported to wane. Our results indicate antipneumococcal immunity may not be optimally maintained using this vaccination strategy in patients with SCD leaving them vulnerable to invasive pneumococcal disease. Many pediatric hematologists stop prophylactic penicillin at 5 years of age making these results alarming. We recommend further investigation into an optimal vaccine schedule and monitoring of antipneumococcal titers in at-risk patients.