An association between Graves' disease (GD) and chronic hepatitis C (C-HC) has been observed both in the presence and the absence of recombinant interferon-α (rIFN-α) treatment. rIFN-α-induced GD is characterized by suppressed thyroid-stimulating hormone levels; normal or elevated free triiodothyronine (FT3) and free thyroxine (FT4) values; the presence of thyroid peroxidase antibodies, antithyroglobulin antibodies, and thyroid receptor antibodies; and high iodine thyroid uptake. In contrast, GD developed during C-HC without rIFN-α is less clearly defined. In this study, we examined two groups of patients: group A, 28 patients with C-HC treated with rIFN-α who developed GD after 1 to 9 months, and group B, 10 patients with C-HC who developed GD without a previous rIFN-α treatment. At the time of GD, both groups started methimazole therapy; thyroid function was reevaluated after 3, 6, 9, and 12 months. Group A patients continued IFN. After 12 months, all patients of group A were euthyroid, and 21 of them (75%) had already stopped methimazole treatment, whereas all patients of group B were euthyroid and only 2 (20%) had stopped methimazole. In conclusion, the data show a better course of GD, with a more precocious and significantly higher number of recoveries in patients with rIFN-α-induced GD than in rIFN-α-unrelated disease. Further studies are needed to establish whether the two types of GD differ not only from a clinical point of view but also because of different underlying pathogenetic mechanisms.