Guinea pigs and rats were exposed to an aerosol of cotton dust (35 mg/m³) for 2 hrs and time courses of the acute pulmonary responses were monitored for 48 hours following exposure. With guinea pigs, a significant increase in breathing rate upon CO₂ challenge was observed 6 hrs after exposure, peaked at 12-18 hrs post-exposure, and remained significantly above control after 48 hrs. Influx of leukocytes into the pulmonary airspaces exhibited a similar time dependence; i.e., there was a significant increase 6 hrs post-exposure which peaked at 18 hrs and remained significantly above control levels for 48 hrs. In contrast, the number of alveolar macrophages obtained by pulmonary lavage declined significantly immediately after exposure and slowly returned to a level slightly above control in 48 hrs. Activation of alveolar macrophages was monitored as zymosan-induced superoxide secretion. Superoxide secretion was significantly elevated 12 hrs after exposure to cotton dust, peaked after 24 hr, and remained significantly above control after 48 hrs. The response of rats to cotton dust exposure differed in both magnitude and time course from that of guinea pigs. In rats, breathing rate upon CO₂ challenge was maximal immediately after cotton dust exposure and rapidly declined thereafter. The number of leukocytes obtained by pulmonary lavage was significantly elevated immediately after exposure, peaked in 6 hrs, and remained significantly above the control level for 48 hrs. In contrast, the number or alveolar macrophages harvested by lavage declined slightly immediately after exposure and returned to a level slightly above control at 48 hrs. Zymosan-induced superoxide secretion from rat alveolar macrophages was unaltered by cotton dust exposure until 18 hrs post exposure when a 22% increase was noted. After this time superoxide release returned to normal levels. Therefore, acute pulmonary responses to cotton dust exposure generally were larger and more prolonged in the guinea pig compared with the rat.