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The acute pulmonary response of male C57BL/6 mice exposed to respirable polymeric hexamethylene diisocyanate biuret trimer aerosol (HDI-BT), a component of polyurethane spray paints, was examined. Mice were exposed to concentrations of 1 and 10 mg/m3 HDI-BT for 5 h and were evaluated 6, 18, 42, 90, 186, and 378 h after the end of exposure. Mice exposed to 1 or 10 mg/m3 HDI-BT exhibited dose-dependent lung function impairment, edema, neutrophilic inflammation, cellular proliferation, and histologic lesions in terminal bronchioles and alveolar ducts. Impairment of pulmonary function, indicated by decreased frequency and increased enhanced pause (Penh), was maximal immediately after exposure and progressively recovered at later time points. Lung weight and lavage fluid protein content peaked at 6 and 18 h after exposure, respectively. Total cells and macrophages recovered in lavage fluid peaked 90 h after exposure. Neutrophils recovered in lavage fluid peaked between 18 and 42 h after exposure. Proliferative lesions, as identified histologically and by bromodeoxyuridine incorporation, were maximal 90 h after exposure. In contrast, no inflammatory cell influx, protein leakage, or lung pathology were observed in mice exposed to 360 ppb HDI monomer vapor. This model will be useful for investigating molecular mechanisms by which HDI-BT causes lung injury, which is known to occur in humans exposed occupationally to this pulmonary toxicant.