OBJECTIVES: The objective was to study the variation in pediatric emergency department (PED) practice patterns for evaluation and management of children with sickle cell disease (SCD) and fever in U.S. children's hospitals. METHODS: A cross-sectional study of visits by children 3 months to 18 years of age with SCD and fever evaluated in 36 U.S. children's hospital PEDs within the 2010 Pediatric Health Information System database. The main outcome measures were the proportions of SCD visits that received evaluation (laboratory testing and chest radiographs [CXRs]) and treatment (parenteral administration of antibiotics) and were admitted for fever. RESULTS: Of the 4,853 PED visits for SCD and fever, 91.7% had complete blood counts (CBCs), 93.8% had reticulocyte counts, 93% had blood cultures obtained, 68.5% had CXRs, and 91.7% received antibiotics. Most (81.4%) patients received the recommended National Heart, Lung and Blood Institute evaluation (CBC, reticulocyte count, and blood culture) and treatment (parenteral antibiotics). In multivariate regression modeling controlling for hospital- and patient-level effects, age groups >/=1 to <5 years (odds ratio [OR] = 0.32, 95% confidence interval [CI] = 0.25 to 0.40) and >/=5 to <13 years (OR = 0.40, 95% CI = 0.32 to 0.50), and those visits that did not have CXRs had lower odds of hospital admission. After adjusting for age, payor status, receipt of laboratory testing, antibiotics, and CXRs, admission rates varied by sevenfold across U.S. children's hospitals (p < 0.001). CONCLUSIONS: Standardization of practice exists across children's hospitals regarding obtaining laboratory studies and administering antibiotics for patients with SCD and fever. However, admission rates vary significantly. Evaluating the causes and consequences of such significant variation needs further exploration to improve the quality of care for patients with SCD.