Interleukin 18 (IL-18) is a pro-inflammatory cytokine, which has been shown to be implicated in the induction of airway hyperresponsiveness (AHR) in murine asthma models. The association of IL-18 with AHR in human bronchial asthma is not clear as yet. As cigarette smoking modifies airway inflammation we aimed to assess the relationship of IL-18 with airway hyperresponsiveness (AHR) in non-smoking versus smoking asthmatics. IL-18 was measured in sputum supernatants obtained from asthmatic (24 smokers and 22 non-smokers) and healthy subjects (16 smokers and 17 non-smokers). All subjects were assessed by spirometry, skin-prick tests to common aeroallergens and bronchial provocation to methacholine (Mch). There was no significant difference in IL-18 levels between healthy and asthmatic smokers and between healthy and asthmatic non-smokers. IL-18 levels in sputum were significantly lower in healthy smokers compared to non-smokers (p=0.048); similarly, in asthmatic smokers as compared to non-smokers (p=0.037). An inverse correlation was found between IL-18 levels, FEV(1) (% pred) (r=-0.495, p=0.043), and PD(20)Mc(h) in non-smoking asthmatics (r=-0.621, p=0.024). A positive correlation was found in smoking asthmatics between IL-18 levels in sputum and FEV(1) (% pred) (r=0.627, p=0.002), FVC (% pred) (r=0.460, p=0.031), and PD(20)Mc(h) (r=0.809, p=0.005). Cigarette smoking reduced IL-18 levels in induced sputum in healthy and asthmatic smokers. IL-18 levels were correlated with airway obstruction and AHR in an inverse way in smoking and non-smoking asthmatics. These results suggest the implication of IL-18 in airway hyperresponsiveness characterizing bronchial asthma, which is modified by smoking.