To investigate the effect of chronic exposure to cigarette smoke on the structure and function of the pulmonary vasculature, we used a guinea pig model of cigarette smoke-induced emphysema, in which groups of guinea pigs were exposed to smoke for periods of 1, 3, 6, and 12 months. We found that the mean pulmonary artery pressure in smokers was increased at one month, a time at which there was no evidence of emphysema. Although the vascular pressures remained elevated, they did not progressively increase, even though there was progressive lung destruction. Pulmonary hypertension was associated with muscularization of the arterioles, seen as an increase in the percentage of small pulmonary vessels with double elastic lamina. We conclude that chronic exposure to cigarette smoke will produce pulmonary hypertension in the guinea pig, and that the hemodynamic changes are accompanied by alteration of the structure of the small pulmonary arterioles and arteries. The apparent dissociation of pulmonary hypertension and emphysema suggests that the pulmonary hypertension is not due to destruction of the lung capillary bed. The etiology of this process may be smoke-induced inflammation with release of vasoactive substances as well as proteolytic enzymes.