Studies of collagen and elastin in pulmonary emphysema have been controversial. The problems involve methodologic differences; often whole lungs have been sampled and the types of emphysema have not been classified. Quantification of collagen and elastin is important since the increase in collagen supports the inflammatory-repair hypothesis of emphysema, which has been recently revived. On the other hand, loss of elastin supports the protease-antiprotease hypothesis. Accordingly, we measured collagen (hydroxy-proline) and elastin (desmosine) in 147 small samples of human lungs removed for cancer. The amount and type of collagen were also assessed histochemically in tissue blocks adjacent to the tissue used for the biochemical analysis. We found that collagen in the homogenates was increased only in irregular airspace enlargement, but histochemically, collagen was consistently increased in centriacinar, distal acinar, and irregular air-space enlargement sections. Elastin was decreased in all grades of panacinar air-space enlargement and also in severe centriacinar air-space enlargement. Our data support both the protease-antiprotease imbalance hypothesis in panacinar and the inflammatory-repair hypothesis in centriacinar, distal acinar, and irregular air-space enlargement.