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Influenza is a respiratory tract disease of viral origin that can cause major epidemics in humans. The influenza virus infects and damages epithelial cells of the respiratory tract and causes pneumonia. Lung lesions of mice infected with influenza virus resembles those seen in humans with influenza, and can result in severe and even fatal pneumonia. In contrast, experimental infection of rats with the virus induces a milder form of the disease, with no mortality. The purpose of the study reported here was to determine the time course of influenza infection and lung injury in Brown Norway (BN), Fischer-344 (F344), and Sprague-Dawley (SD) rats to ascertain whether genetic background impacts susceptibility to infection and host responses. Rats of each strain were inoculated intranasally with 10,000 plaque-forming units of rat-adapted influenza virus (RAIV), and lungs were assessed at postinoculation hour (PIH) 2, 24, 48, 72, and 144 for viral titer, inflammatory cells, pro-inflammatory cytokines, and biochemical indicators of lung edema (protein) and injury (lactate dehydrogenase [LD] activity). Virus titer peaked at PIH 24, and was 100-fold higher in the F344 and SD, compared with the BN strain. Alveolar macrophages, LD activity, and total protein concentration were higher in the BN rats, whereas neutrophil numbers and interleukin 6 and tumor necrosis factor-alpha activities were greatest in the bronchoalveolar lavage fluid of F344 and SD rats. The results indicate that F344 and SD rats respond in similar manner to viral infection, whereas viral replication was more limited in BN rats and was associated with a different profile of pulmonary cells.