Guinea pigs were exposed by nose only for 3 hr/day for 6 days to freshly formed zinc oxide (ZnO) particles (projected area diameter = 0.05 micron, sigma g = 2.0) at 5 mg/m3, the currently recommended threshold limit value (TLV). Ventilation, lung mechanics, lung volumes, and diffusing capacity for carbon monoxide (DLCO) in anesthetized, tracheostomized animals at 1, 24, 48, or 72 hr after the end of the last exposure were evaluated. At the same time intervals lung weight, lung fluid content, respiratory epithelial permeability to horseradish peroxidase, gross and microscopic appearance, and [3H]thymidine labeling of nuclei of bronchial and bronchiolar epithelial cells in other groups of animals were measured. Vital capacity, functional residual capacity, alveolar volume, and DLCO were all decreased following the last exposure and did not return to normal values by 72 hr. Increases in flow resistance and decreases in compliance and total lung capacity returned to normal by 72 hr. Lung weights were elevated due to inflammation involving the proximal portion of the alveolar ducts and adjacent alveoli. These changes were still present at 72 hr. [3H]Thymidine labeling of bronchiolar epithelial cell nuclei was increased for 48 hr. Respiratory epithelial permeability to horseradish peroxidase was not affected by the exposures. These results suggest that the current TLV for ZnO may not be adequate.