Wound healing and tumor stroma generation share several important properties, including hyperpermeable blood vessels, extravasation of fibrinogen, and extravascular clotting. In both, the deposits of fibrin gel serve initially as provisional stroma and later are replaced by granulation tissue. Proteoglycans (PG) are also important constituents of the extracellular matrix, but their composition and role in healing wounds and tumor stroma generation are poorly understood. The authors used immunohistochemical and biochemical methods to investigate the dermatan sulfate proteoglycan (DSPG) and chondroitin sulfate proteoglycan (CSPG) composition of healing skin wounds and solid tumors. By immunohistochemistry, the great majority of normal guinea pig and human dermis stained weakly for CSPG and strongly for decorin. In contrast, the granulation tissue of healing skin wounds and scars stained intensely for CSPG and weakly or not at all for decorin; however decorin staining was restored to normal intensity after digestion with chondroitin ABC lyase, suggesting that decorin antigenic sites had been masked by glycosaminoglycan (GAG) chains. Like wounds, the stroma of several carcinomas (line 1 guinea pig, human breast, colon, basal cell, and squamous) stained strongly for CSPG and weakly or not at all for decorin, but decorin staining developed after chondroitin ABC lyase digestion. Thus healing wounds and tumor stroma express a common pattern of altered PG staining, adding another to the properties these pathologic entities share. Proteoglycans extracted from healing wounds after in situ labelling with [35S] Na sulfate contained more CSPG than normal dermis with significantly longer GAG chains. Granulation tissue also synthesized more DSPG than normal skin, with greater heterogeneity and longer GAG chains. These alterations in PG synthesis correlate with the cell proliferation, migration, and collagen synthesis that accompany wound healing and may provide clues to the mechanisms responsible for both wound healing and tumor stroma generation.