Study Objectives Pulmonary involvement is a major cause of morbidity and mortality in patients with sickle cell disease (SCD). Although a high prevalence of airway hyperresponsiveness (AHR) has been reported, there are no studies demonstrating the relationship between AHR and acute chest syndrome (ACS) in adults with SCD. We investigated AHR prevalence, lung function abnormalities, and the relationships of these variables with ACS in SCD patients. Method Thirty-one adult patients without asthmatic symptoms were compared with 31 matched controls. Expiratory flow rates, lung volumes, carbon monoxide diffusion capacity (DLCO), and methacholine provocation test (MPT) results were assessed. Results Forced vital capacity (FVC), forced expiratory volume in one second, forced expiratory flow rate at 25% to 75% of FVC (FEF25%-75%), peak expiratory flow rate, total lung capacity, and DLCO values were significantly lower in the patient group than in the controls. No significant difference in pulmonary function test results was found between patients with and without a history of ACS. Fifteen patients with SCD (48%) and only 5 controls (16%) had AHR (p = 0.007). A significant correlation was found between the number of ACS episodes and MPT positivity (r = 0.379, p = 0.035). The FEF25%-75% values were significantly lower in patients with positive MPT results than in patients with negative MPT results (p = 0.027). Conclusion The prevalence of AHR was high in adult patients with SCD. A significant correlation was found between AHR and recurrent ACS episodes. Anti-inflammatory controller agents can be used routinely to decrease pulmonary morbidity associated with SCD, even in the absence of asthmatic symptoms.