Progressive restrictive defect with increasing age, obstructive lung disease, and bronchodilator responsiveness have been reported in sickle cell disease (SCD). Because airway hyperreactivity (AHR) can be underestimated when assessed by bronchodilator responsiveness in patients with normal baseline lung function, the aim of this study was to investigate the prevalence of AHR in SCD by cold-air bronchial provocation testing, and to assess whether AHR can be present in symptom-free patients with SCD. Forty patients aged 6 to 19 years (mean, 10.7 years +/- 3.5 SD) performed pulmonary function tests. Eighteen were known to have a history of reactive airway disease (RAD group), and 22 had no known history of RAD (non-RAD group). A control group, aged 6 to 7 years (mean, 10.5 +/- 3.1 years), consisted of 10 siblings of the non-RAD SCD group. There were no significant differences in age and height among the groups. If the forced expiratory volume in 1 second (FEV1) was greater than 70%, cold air challenge (CACh) was performed; if the FEV1 was less than 70%, aerosolized bronchodilator therapy was given. A decrease in FEV1 of more than 10% after CACh or an increase in FEV1 of 12% or greater after bronchodilator inhalation was considered evidence of AHR. In the RAD group, the total lung capacity was 88.9% +/- 14.0% of race-corrected predicted values, the forced vital capacity was 91.2% +/- 12.6%, and FEV1 was 85.3% +/- 16.2%. The mean maximal percent fall in FEV1 after CACh (n = 13) was 18.5% +/- 9.6% and was greater than 10% in 11 of 13 patients. The mean increase in FEV1 after bronchodilator therapy (n = 5) was 11.5% +/- 8.3%, and it was greater than 12% in 4 of 5 patients. In the non-RAD group the baseline total lung capacity was 101.6% +/- 11.7%, forced vital capacity was 95.5% +/- 10.2%, and FEV1 was 93.3% +/- 13.2%. The mean maximal percent fall in FEV1 after CACh (n = 19) was 14.1% +/- 8.8% and was greater than 10% in 13 of 19 patients. The mean increase in FEV1 after bronchodilator therapy (n = 3) was 14.7% +/- 11.3%, and was 12% of greater in 1 of 3 patients. In the control group the baseline total lung capacity was 105.7% +/- 12.1%, forced vital capacity was 96.2% +/- 11.1%, and FEV1 was 92.9% +/- 10.3%. The mean maximal percent fall in FEV1 was 5.0% +/- 2.5%, and was greater than 10% in none of 10 patients. The prevalence of AHR in the control group, the RAD group, and the non-RAD group was zero, 83%, and 64%, respectively (p < 0.0001). The overall prevalence in the SCD group was 73%. We conclude that there is a high prevalence of AHR in children with SCD and that airway hyperreactivity may exist in patients with SCD even in the absence of the clinical symptoms of RAD. AHR may be a significant component of sickle cell lung disease.