Objective: To delineate the natural history of splenic complications other than the loss of splenic function in children with sickle cell disease (SCD), we performed a retrospective chart review of patients with SCD treated at the Texas Children’s Hospital. Methods: We determined the dates of diagnoses of splenic complications, the number of ASSC events, and hydroxyurea treatment in patients with SCD. We also examined the association of hydroxyurea therapy with the onset and severity of ASSC. Results: The cumulative prevalence of splenic complications was 24.7% for splenomegaly, 24.2% for ASSC, 9.6% for hypersplenism, and 5.6% for splenectomy. The cumulative prevalence of all splenic complications was highest in patients with hemoglobin Sβ ⁰ (69.2%), intermediate in hemoglobin SS (33.3%), low in hemoglobin SC (9.0%), and non-existent in hemoglobin Sβ ⁺. The overall event-rate of ASSC was 8.3 per hundred patient-years. The event-rate was 28.4 in the hemoglobin Sβ ⁰, 10.9 in hemoglobin SS, and 3.5 in hemoglobin SC Patients with hemoglobin SS and hemoglobin Sβ ⁰ on hydroxyurea therapy had a significantly higher occurrence of ASSC than those who were not, with event-rates of 14.2 and 3.1, respectively. The event-rate was also higher for children who started hydroxyurea before age 2 years than for those who started after this age (19.8 and 9.2 respectively). Conclusions: The prevalence and severity of splenic problems vary widely between different sickle cell genotypes, with hemoglobin Sβ ⁰ having the most severe complications. Hydroxyurea therapy is strongly associated with incidence of ASSC, particularly when initiated before two years of age.