To determine the occurrence and magnitude of airway hyperresponsiveness (AHR) in children with sickle cell anemia (SCA) who had or had not had acute chest syndrome (ACS) episodes. A subsidiary aim was to determine whether cold air and exercise challenge testing gave similar results in children with SCA. AHR would be greater in SCA children who had had an ACS episode compared to those who had not. Prospective observational study. Forty‐two SCA children (median age of 11.5 [range 6.1–16.8] years); 12 children had been previously hospitalized for an ACS episode. AHR was assessed by the change in forced expiratory volume in 1 sec (FEV₁) to a cold air challenge and in a subset of the children to an exercise challenge. A positive result to either challenge was deemed to have occurred if the FEV₁ fell by at least 10% from the pre‐challenge baseline. The magnitude of change in FEV₁ following the cold air challenge was similar in children who had or had not had an ACS episode. Six children had a positive response to the cold air challenge (AHR); none had had an ACS hospitalization. Similar proportions of children responded to the cold air and exercise challenge and the magnitude of response to the two tests was similar. Some children, however, responded only to a cold air challenge and others only to an exercise challenge. SCA children who had had an ACS hospitalization episode compared to those who had not were not more likely to respond to a cold air challenge. Importantly, if AHR is to be correctly diagnosed, some SCA children will require to undergo both cold air and exercise challenge testing. Pediatr Pulmonol. 2007; 42:272–276. © 2007 Wiley‐Liss, Inc.