The palmar fascial tissues of more than 400 patients with Dupuytren's disease were studied biochemically and compared with normal tissue obtained from more than 100 patients who were undergoing hand surgery for other reasons. No alterations of the molecular structure or the state of macromolecular aggregation of the collagen in Dupuytren's disease were detected by wide or low-angle x-ray diffraction studies or by transmission electron microscopy. Major biochemical changes in the palmar fascia affected by Dupuytren's disease included increased collagen and hexosamine contents and the presence of galactosamine in the most severely involved tissue. Type-III collagen, which is virtually absent from normal adult palmar fascia, was abundant in the tissue of patients with Dupuytren's disease. Post-translational modifications included a very elevated hydroxylysine content, an increase in the total number of reducible cross-links, and the appearance of hydroxylysinohydroxynorleucine (virtually absent from normal palmar fascia) as the major reducible cross-link. Even palmar fascia from patients with Dupuytren's disease that appeared grossly and histologically normal showed the same biochemical changes, albeit to a lesser extent. All of these biochemical changes are similar to those that occur during the active stages of connective-tissue wound repair. This includes the rapid synthesis and turnover of collagen which leads to newly synthesized, immature collagen being more abundant in the involved tissue than in normal tissue. There is no evidence that the gross, macroscopic contracture of the palmar fascia in Dupuytren's disease is due to shortening, plication, or contraction of the collagen fibrils or fibers present in the tissue at the onset of the disease or synthesized during its development. Instead, we propose that the gross contracture (shortening) of the palmar fascia in Dupuytren's disease is due to an active cellular process that progressively draws the distal extremities of the affected tissue closer together at the same time that the original tissue is being replaced. The result of these two processes is simply a shorter, smaller piece of tissue fabric containing collagen molecules, fibrils, and fibers of normal length and organization, but with pretranslational and posttranslational modifications similar to those observed in collagens during the active stages of connective-tissue repair in general.