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Glycosaminoglycan (GAG) infiltration of the skin is a feature of hyperthyroidism, hypothyroidism, pretibial myxedema, scleromyxedema, and scleredema. We investigated the pathogenesis of the GAG deposits using light microscopy, histochemical digestion with a series of GAG-specific enzymes, and electron microscopy. Hyaluronic acid was the main GAG in all the conditions and in normal skin. Furthermore, there was minimal histologic variability of GAG dermal distribution. A striking distinguishing feature involved dermal fibroblast activity, which appeared normal or inactive in thyroid disorders and hypertrophic and/or hyperplastic in scleromyxedema and scleredema. Thus, the acquired cutaneous mucinoses exhibit similar skin GAG distribution and biochemical composition. The morphologic differences in fibroblastic activity suggest that the mucinoses of scleredema and scleromyxedema represent a local process, whereas the GAG infiltration of thyroid diseases may have a systemic origin.