Morphometric analysis was performed on alveolar macrophages obtained by bronchopulmonary lavage of rats exposed to tobacco smoke for periods up to 60 consecutive days. Smoke dosage levels were adjusted so as to be comparable to those of human smokers. Size distributions were obtained for the lavaged macrophage populations of treated and age-matched control animals following 30 and 60 days of smoke exposure. Electron microscopic stereology was used to quantitate alterations in the ultrastructure of the same macrophage preparations. Several significant changes were observed in macrophage morphology following exposure to tobacco smoke, with an estimated mean cell volume more than twice that of controls following 60 days of smoking. After 30 and 60 days of exposure there was a 10- and 16-fold increase, respectively, in the volume density of cytoplasmic lipid inclusions. The surface to volume ratio of the cells and the lysosomal volume density were reduced in macrophages from smoke-exposed animals. A possible relationship between the incidence of lysosomes and the accumulation of cytoplasmic lipid in treated cells is discussed.