BACKGROUND: Acute chest syndrome (ACS) is a frequent cause of morbidity and leading cause of death among individuals with sickle cell disease. Yet, ACS in hemoglobin SC disease is not well characterized. The objective of this study was to compare the presentation and clinical course of ACS in individuals with hemoglobin SC disease to that observed in individuals with hemoglobin SS disease. PROCEDURE: We retrospectively reviewed 71 inpatient episodes of ACS in patients with hemoglobin SC disease over a 20-year period. Continuous and categorical data from index cases were compared with that from 71 control cases of ACS in patients with hemoglobin SS disease. RESULTS: Median length of hospitalization was shorter for hemoglobin SC episodes when compared to hemoglobin SS episodes (3.0 vs. 5.0 days, P < 0.001). In comparison to hemoglobin SS patients, a greater proportion of hemoglobin SC patients had a previous history of asthma or wheezing (50.7 vs. 33.8%, OR = 2.01 [1.02-3.96], P = 0.041) and a respiratory complaint of wheeze (11.3 vs. 2.8%, OR = 4.38 [0.90-21.4], P = 0.049). In our multivariate regression model, time to ACS diagnosis and total number of days of oxygen supplementation were independent predictors of length of hospitalization in both hemoglobin SC and SS episodes of ACS. CONCLUSIONS: ACS appears to be less severe in children with hemoglobin SC disease compared to that in children with SS disease. Asthma and wheezing may represent more significant risk factors for the development of ACS in children with hemoglobin SC disease.