Experiments were performed to serve as a basis for analyzing the immune responses of the host to a viral respiratory tract infection. In a comparative study, inbred BALB/c and nude (athymic mice bred on a BALB/c background) mice were infected intranasally with mouse adapted A/Port Chalmers/1/73 influenza virus. Survival was prolonged in the nude mice (16 days vs 10 days for BALB/c mice, t = 3.5, p less than 0.01), but significantly fewer of the nude mice survived 21 days (16% vs 42% of BALB/c mice). In addition, virus persisted longer in the lungs of nude mice (5.8 log10 of infectious virus on day 21 vs no detectable virus in BALB/c mice) and lung pathology progressed more slowly but lasted longer in nude mice, as measured by immunofluorescent and histologic examination of pulmonary tissue. Antibody production was significantly lower and there was no cytotoxic T cell response detected in lymphoid cells prepared from the spleens, peripheral blood, or the lung after the infection of nude mice. A significant increase in the number of lymphocytes isolated from the lung was observed by day 7 (t = 5.8, p less than 0.001) in the BALB/c mice but not until day 14 (t = 4.9, p less than 0.001) in the nude mice. Lymphocytes from nude mice did not respond to influenza virus antigens or Concanavalin A (Con A) but did respond to lipopolysaccharide (LPS), whereas lymphocytes from BALB/c mice responded to all 3 preparations.