Rationale: Studies have shown that cigarette smoke impacts respiratory host defense mechanisms; however, it is poorly understood how these smoke-induced changes impact the overall ability of the host to deal with pathogenic agents. Objective: The objective of this study was to investigate the impact of mainstream cigarette smoke exposure on immune inflammatory responses and viral burden following respiratory infection with influenza A. Methods: C57BL/6 mice were sham- or smoke-exposed for three to five months and infected with either 2.5x10³ pfu (low dose) or 2.5x10⁵ pfu (high dose) influenza virus. Measurements and Main Results: While smoke exposure attenuated the airways inflammatory response to low dose infection, we observed increased inflammation in smoke- compared to sham-exposed mice following infection with high dose influenza, despite a similar rate of viral clearance. The heightened inflammatory response was associated with increased expression of TNF, IL-6 and type 1 interferon in the airway, and increased mortality. Importantly, smoke exposure did not interfere with the development of influenza-specific memory responses; sham- and smoke-exposed animals were equally protected upon viral re-challenge. Conclusion: Our study suggests that in mice cigarette smoke affects primary antiviral immune-inflammatory responses, while secondary immune protection remains intact.