To determine whether smoke could directly affect the cells of the small airways and the small vessels, we exposed Sprague-Dawley rats to the whole smoke of 7 cigarettes/day for 1, 2, or 7 days. Three hours before the rats were killed, 5-bromo-2'-deoxyuridine (BrdU) was administered. Labeled nuclei were counted in histological sections stained with antibodies to BrdU. In smokers, pulmonary artery walls at the level of the membranous bronchioles (MB), respiratory bronchioles (RB), and alveolar ducts (AD) showed significant increases in labeled nuclei at all three times; increases in endothelial labeling were only present in vessels associated with AD. Significantly increased labeling was also seen in the epithelium and walls of MB and RB themselves at all time periods. However, there was no correlation between labeling indexes in matched pairs of airways and vessels. Smoke had no effect on the labeling of mesothelial and submesothelial cells. We conclude that cigarette smoke rapidly causes proliferation of intrinsic cells in the airways and small vessels; this effect may lead eventually to airway wall muscular hyperplasia and fibrosis (small airways disease) and to vascular changes associated with pulmonary hypertension. However, the lack of correlation between labeling indexes in the vessels and airways suggests that different mediators are involved at these two sites. At least over the time course of this experiment, smoke does not cause proliferation of mesothelial or submesothelial cells.