Glycosaminoglycans (GAGs), also known histologically as dermal mucin, accumulate in several inflammatory skin conditions. Because different GAG species have distinct immunologic effects, the authors examined two GAGs, hyaluronan (HA) and chondroitin sulfate (CS), using specific stains in cutaneous lupus erythematosus (CLE) and dermatomyositis (DM). In the dermis of one CLE subtype, tumid LE (TLE), they found only increased HA, but both HA and CS were significantly elevated in another CLE subtype, discoid LE (DLE). DM lesional dermis accumulated mainly CS but not HA. The authors then used glycomic gene expression microarrays to assess the expression of HA- and CS-related genes in CLE skin. Real-time quantitative PCR confirmed significantly increased expression of HAS2, CHSY1, and C4ST1 in the combined groups of CLE lesions (n = 8) compared to healthy controls (n = 4). Thus, the increase in HA in CLE presumably results from upregulation of HAS2, whereas CHSY1 and C4ST1 appear to contribute to increased CS. Based on their known immunomodulatory effects in other systems, HA and CS may thus participate in the pathophysiology of these inflammatory skin conditions.