Hartley guinea pigs, Fischer-344 rats, and B6C3F1 mice of both sexes were exposed to varying concentrations of methyl isocyanate (MIC) vapor with the highest concentration being 20.4 ppm for rats and mice and 10.5 ppm for guinea pigs. A control group for each species was exposed to air only. All animals were exposed for a duration of 6 hr, and survivors were sacrificed 14 days following exposure. The respiratory tract was removed and examined microscopically from all animals. Guinea pigs were more sensitive to the MIC vapor than were rats which were in turn more sensitive than mice. Gross lesions encountered in many of the animals that died consisted of nasal discharge, often blood tinged, and discoloration of the lungs. Microscopic lesions included acute necrosis of epithelial lining throughout the respiratory tract in animals that died shortly after exposure coupled with congestion, edema, and inflammation. A microscopic lesion which appeared unique to guinea pigs was bronchiolitis obliterans where the necrosis and inflammation had completely closed the bronchioles. Additional microscopic lesions observed in some animals that died or were sacrificed at the end of the study (postexposure Day 14) consisted of squamous metaplasia of respiratory epithelium in the nasal cavity, which extended into the larynx, trachea, and, in some cases, the bronchi. In addition, epithelial regeneration throughout the tract and submucosal fibroplasia in the trachea, bronchi, and bronchioles were observed, the latter lesion being primarily confined to rodents. No animals exposed to 2.4 or 1.0 ppm of MIC vapor died following exposure. There were minimal microscopic lesions at sacrifice in the 2.4 ppm-exposed animals from all three species. Only in guinea pigs were there lesions in the 1.0-ppm group attributed to MIC vapor exposure.