A distinctive histopathological feature associated with thyroid-associated ophthalmopathy is the disordered accumulation of the glycosaminoglycan, hyaluronan, in orbital connective tissues. This often occurs in the context of dramatic inflammation and tissue remodeling. Orbital fibroblasts exhibit a novel phenotype including exaggerated responses to cytokines. Here, we report for the first time the ability of IgG isolated from the sera of patients with Graves' disease (GD-IgG) to provoke in orbital fibroblasts the synthesis of hyaluronan. The effect of GD-IgG can be reproduced by IGF-I, appears to be mediated through the IGF-I receptor, and is abolished with glucocorticoid treatment. TSH failed to influence the synthesis of hyaluronan. In contrast to the effects in GD fibroblasts, cultures derived from donors without known thyroid disease fail to respond to GD-IgG or IGF-I. The observation that hyaluronan production is induced by GD-IgG in fibroblasts suggests that the IGF-I receptor and its activating antibodies may represent a key pathway through which important pathogenic events in thyroid-associated ophthalmopathy are mediated.