Background: Smoke has been proved to be one of the most dangerous ingredients leading to the unsatisfying treatment response of asthmatics to inhaled corticosteroids (ICS) therapy. Macrolides, a class of antibiotics, possess the traits of immunomodulation and anti-inflammation besides antimicrobial activity. Given that studies on the efficacy of macrolides on the refractory asthma patient have diverting conclusions, this article was carried on to investigate the effects of macrolide on the airway inflammation of smoke-exposed asthmatic mice. Methods: BALB/c mice were chosen to be the subjects of this study. They were raised to establish asthma model (OVA group); and one asthma group were exposed to the smoke (SEA group), one asthma group were treat with clarithromycin (CAM group) after smoke exposure. Control group mice were used as parallel comparison. Total inspiratory resistance (RL), expiratory resistance of the lung (Re) and lung compliance (Cdyn) were the main index to evaluate airway hyperresponsiveness (AHR). The histopathological change was studied to assess lung tissue inflammation. Cell counts in bronchoalveolar lavage fluid (BALF) were also tested to represent airway inflammation. IL-4 and CXCL1 in BALF and serum were also used to evaluate the airway inflammation. Histone deacelytase2 (HDAC2) activity of lung tissues was measure by assay kit. HDAC2 expression in the lung tissue had been detected by western blot. Results: Re, RL and Cdyn were monitored to represent airway responsiveness. All of the three indicators in SEA group were significantly different from control group, while clarithromycin improved airway responsiveness and the three indicator were statistically significant (P<0.01). Histopathology observation had showed massive infiltration of inflammatory cells in both OVA group and SEA group, while inflammation infiltration attenuated in CAM group. Total cell counts in SEA group was much higher than that in CAM group (P=0.019), so were neutrophils (P=0.022) and eosinophils (P=0.042); while macrophages in SEA group decreased when compared to CAM group (P=0.026), IL-4 and CXCL1 level in CAM group were significantly decreased in comparison to those in SEA group (P=0.031, P=0.017). HDAC2 activity in SEA group decreased significantly when compared to control group (P=0.010); while HDAC2 activity in CAM group was improved and significantly better than that in SEA group (P=0.038). The expression of HADC2 in CAM group improved significantly when compared to that in SEA group (P=0.022). Conclusions: Clarithromycin could improve AHR and attenuate airway inflammation in smoke exposed asthmatic mice which may involve HDAC2. Macrolides might have the potential to serve as the adjunctive treatment to some refractory asthmatics who are smokers or passive smokers.