BACKGROUND: Since cigarette smoking is an important risk factor for respiratory infections and alters the immune response, the severity of influenza illness and the immunogenicity of influenza vaccination may differ between cigarette smokers and non-smokers. This study investigated the effect of cigarette smoke exposure on the severity of influenza illness and vaccine-induced antibody production in mice. MATERIALS AND METHODS: Cigarette smoke exposed (CE) and non-cigarette smoke exposed (NCE) mice were infected with mouse-adapted influenza A/PR8/8/34 (H1N1). Influenza virus was quantified in bronchoalveolar lavage fluid by real-time polymerase chain reaction and the lung pathology was examined to investigate the influence of smoke exposure on the severity of illness. To assess immunogenicity, hemagglutination inhibition antibodies were measured in pre- and post-influenza vaccination blood samples from CE and NCE mice. RESULTS: Influenza viral proliferation was higher and inflammatory changes such as macrophage infiltration in the alveolar space and necrotizing bronchitis were more pronounced in CE mice, compared with controls. Vaccine-induced immunogenicity was achieved in both CE and NCE mice. CONCLUSIONS: Cigarette smoke exposure enhanced influenza viral replication and the inflammatory changes associated with influenza illness, but had no significant effect on vaccine-induced immunogenicity.