We have previously shown that chronic cigarette smoke exposure produces emphysema and airflow obstruction in the guinea pig. To further examine the changes in the connective tissue matrix associated with emphysema in this model, we used ultrastructural morphometry to determine the volume proportions of collagen and elastin in the alveolar walls of animals exposed to smoke or air (control) for 1, 3, 6, and 12 mo. After 1 mo of smoke exposure, there was a statistically significant (P < 0.001) decrease in the volume proportion of collagen in the smoke-exposed animals, whereas by 6 and 12 mo of smoke exposure, the proportion of collagen had significantly (P < 0.02, P < 0.03, respectively) increased. The volume proportion of elastin was increased in the smoke-exposed animals at the 12-mo time period. While our results do not exclude reorganization of elastin within the alveolar wall, we conclude that, in this model, cigarette smoke-induced emphysema appears to be associated with collagen breakdown and repair. We suggest that the currently accepted proteolysis-antiproteolysis theory is too narrow in its focus on elastin destruction as the major contributor to emphysema and should be broadened to the concept that smoke-induced emphysema reflects breakdown and resynthesis (possibly overproduction in the form of scarring) of a variety of connective tissue proteins in addition to elastin.