Recent studies have emphasized the presence of airway hyperreactivity (AHR) in children with sickle cell disease (SCD). However, various tests for the detection of AHR have yielded distinctly different results in these patients. This study identified AHR via a methacholine challenge test (MCT) in a group of children with SCD (31 patients; age range, 6–16 years). The results of pulmonary function tests (PFTs) in patients with SCD and age‐matched controls (30 healthy children) were investigated and compared. A positive methacholine challenge result was noted in 25 patients (77.5%). We found that when compared with controls, the children with SCD had lower forced vital capacity (FVC) and forced expiratory volume in 1 sec (FEV₁) and that both their forced expiratory flow at 25–75% of the FVC (FEF_25–75) and their FEV₁/FVC ratio were not statistically significantly different from those of the controls. The statistically significant differences remained after treatment with a bronchodilator agent, but the changes in the FVC, FEV₁, and FEF_25–75 in response to bronchodilator treatment did not differ with statistical significance between the two groups. There was a negative correlation between the number of ACS attacks and the percent predicted of the FEV₁ and the FEV₁/FVC ratio. We found that the MCT reveals a high incidence of AHR in patients with SCD, regardless of whether those individuals have ACS. Pediatr Pulmonol. 2007; 42:1187–1192. © 2007 Wiley‐Liss, Inc.