The density of zinc-iodide-osmium (ZIO) positive pulmonary Langerhans dendritic cells (LC) was increased about 20-fold in mice after passive exposure to tobacco smoke. This was associated with pulmonary changes consistent with the cigarette smoking-related clinical syndrome in humans, pulmonary Langerhans cell granulomatosis. The major feature was an interstitial peribronchial granuloma. The cellular infiltrate of the granuloma (lymphocytes, plasma cells, eosinophils, clusters of large histiocyte-like cells and macrophages) extended into the adjacent alveolar septum forming a star-shaped lesion. The histiocyte-like cells were large with pale acidophilic cytoplasm and many ill-defined short dendrites extending from the cell membrane. Bronchial epithelial metaplasia also developed. The interstitial changes were followed by the development of proliferative alveolar and bronchial lesions in 2 mice. The zinc-iodide-osmium positive cells were consistent with la positive pulmonary dendritic cells and their ultrastructure was similar to that of pulmonary Langerhans cells. After ceasing exposure to tobacco smoke the density of pulmonary Langerhans cells returned to that of the control level; interstitial granulomatous lesions disappeared, but the bronchial epithelial metaplasia did not reverse. Tobacco smoke exposure of mice produces interstitial granulomatous inflammation similar to Langerhans cell granulomatosis in humans. The elevated level of pulmonary Langerhans cells implicate these cells in the pathogenesis of these lesions.