Thyroid eye disease (TED) is a debilitating disorder characterized by the accumulation of adipocytes and hyaluronan (HA).Production of HA by fibroblasts leads to remarkable increases in tissue volume and to the anterior displacement of the eyes. Prostaglandin D 2 (PGD 2 ), mainly produced by mast cells, promotes orbital fibroblast adipogenesis. The mechanism by which PGD 2 influences orbital fibroblasts and their synthesis of HA is poorly understood. We report here that mast cell-derived PGD 2 is a key factor that promotes HA biosynthesis by orbital fibroblasts. Primary orbital fibroblasts from TED patients were isolated and used to test the effects of PGD 2 , prostaglandin J 2 , as well as prostaglandin D receptor (DP) agonists and antagonists on HA synthesis. The expression of HA synthase (HAS), hyaluronidase, DP1, and DP2 mRNA levels was assessed by PCR. Small interfering RNAs against HAS1 or HAS2 were used to assess the importance