The present study determined the morphogenesis of upper respiratory tract disease in rats following infection with a rat-adapted influenza virus. Sixty-eight 60-day-old, male F344 rats were infected by intranasal inoculation and necropsied at days 1, 2, 4, 7, 14, and 28 post-inoculation (PI). Responses to infection were studied by routine light microscopy for histopathologic changes and immunocytochemistry for localization of viral antigen. Severe infection-induced changes involved the respiratory epithelium and underlying lamina propria, and the nasal-associated lymphoid tissue, with minimal involvement of the transitional epithelium. The lesions were most severe on the septum and the medial aspect of the nasoturbinates. Viral antigen, located in the respiratory epithelium of affected regions at days 1 and 2 PI, was associated with neutrophilic infiltration and epithelial necrosis and erosion. At day 4 PI, an infiltrate of lymphocytes, macrophages, and fewer neutrophils was present, often accompanied by epithelial regeneration. Changes in the nasal-associated lymphoid tissue were evaluated using morphometric analysis and consisted of hyperplasia (days 4 to 7 PI) followed by progressive involution (days 14 to 28 PI). Mild lesions associated with foci of viral antigen were also observed in the nasal olfactory epithelium on days 1, 2, and 4 PI. The changes observed in the present study indicate the potential value of rat-adapted influenza virus infection as a model of human influenza.