Study objective: To determine the diagnostic value of anemia, RBC morphology, and reticulocyte count for differentiating patients with sickle cell trait from those with sickle cell disease, who have acute medical or surgical conditions and a positive sickle cell screen. Design: Retrospective chart review. Setting: A midwest urban children's hospital with 220 beds and 36, 000 emergency department visits per year. Participants: One hundred six patients with sickle cell trait and 152 patients with sickle cell hemoglobinopathies. Results: Anemia was observed significantly more often in patients with sickle cell disease compared with sickle cell trait ( P < .001) at all ages 3 months and older. However, anemia alone as a diagnostic test lacked high sensitivity and specificity in children less than 4 years old. Sensitivity approached 100% with the presence of anemia, abnormal RBC morphology, or reticulocyte count of more than 2%. Conclusion: Absence of anemia alone does not exclude the diagnosis of sickle cell disease in children less than 4 years old. To differentiate trait from sickle cell disease, we recommend determination of not only hemoglobin adjusted for age but also of RBC morphology and reticulocyte count on all children presenting with acute medical and surgical conditions and a positive sickle cell screen.