<title>Abstract</title>IL-17A and IL-17F are both involved in the pathogenesis of neutrophilic inflammation observed in COPD and severe asthma. To explore this, mice deficient in both <italic>Il17a</italic> and <italic>Il17f</italic> and wild type (WT) mice were exposed to cigarette smoke or environmental air for 5 to 28 days and changes in inflammatory cells in bronchoalveolar lavage (BAL) fluid were determined. We also measured the mRNA expression of keratinocyte derived chemokine (<italic>Kc</italic>), macrophage inflammatory protein-2 (<italic>Mip2)</italic>, granulocyte–macrophage colony stimulating factor (<italic>Gmcsf)</italic> and matrix metalloproteinase-9 (<italic>Mmp9</italic> ) in lung tissue after 8 days, and lung morphometric changes after 24 weeks of exposure to cigarette smoke compared to air-exposed control animals. Macrophage counts in BAL fluid initially peaked at day 8 and again on day 28, while neutrophil counts peaked between day 8 and 12 in WT mice. Mice dual deficient with <italic>Il17a and 1l17f</italic> showed similar kinetics with macrophages and neutrophils, but cell numbers at day 8 and mRNA expression of <italic>Kc</italic>, <italic>Gmcsf</italic> and <italic>Mmp9</italic> were significantly reduced. Furthermore, airspaces in WT mice became larger after cigarette smoke exposure for 24 weeks, whereas this was not seen dual <italic>Il17a and 1l17f</italic> deficient mice. Combined <italic>Il17a</italic> and <italic>Il17f</italic> deficiency resulted in significant attenuation of neutrophilic inflammatory response and protection against structural lung changes after long term cigarette smoke exposure compared with WT mice. Dual IL-17A/F signalling plays an important role in pro-inflammatory responses associated with histological changes induced by cigarette smoke exposure.