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Virus population dynamics in the lungs, trachea, and nasopharynx of Swiss-ICR mice were studied after respiratory challenge with mouse-adapted preparations of strain A2/Aichi/2/68 influenza virus. Markedly higher doses of virus were required to produce infection with nasopharyngeal challenge than with bronchoalveolar challenge. In all of the infections, the highest virus concentrations were observed in the lungs. Peak concentrations in the trachea were lower than in the lungs but higher than in the nasopharynx. Decreasing virus levels were observed by 120 h after challenge and were generally below detectable levels by the end of 10 days. A compartmental model of a single mathematical form was developed which provided close fits of the virus concentration measurements regardless of the challenge dose, site of initial deposition, or respiratory tissue considered. The model includes seven compartments with five associated rate parameters. The application of compartmental modeling techniques and expression of the virus population dynamics in mathematical terms is regarded as a new approach to the study of the pathogenesis of infections.