Seventy-nine patients (40 males, 39 females) were enrolled in a prospective study of lymphoblastoid interferon-α (IFN), 3-5 MU three times weekly. They were randomly assigned to receive either 12 months of IFN therapy, or to 6 months of observation followed by 6 months of IFN therapy. The thyroid functional and immunological status was checked every other month during and after treatment. Before treatment, antithyroid antibodies were found in 6 patients (7.5%). Two were hypothyroid and were excluded from the study before starting IFN therapy. Seventy-seven patients received IFN therapy. Of these, thyroid abnormalities appeared in 6 (7.5%). Hyperthyroidism was observed in 3 patients. Two recovered within a few months, but 1 developed subsequent hypothyroidism. Hypothyroidism was observed in 2 patients. TSH blood values were persistently abnormal, but thyroid antibody levels remained increased and fluctuating. Thyroid function usually recovered within a few months; but 2 patients required hormonal therapy and 1 was treated with carbimazole. In 1 patient, a small thyroid papillary carcinoma was observed, but no evidence of relationship with the liver disease or with IFN therapy was found. In a patient with chronic hepatitis C, systematic thyroid assessment should be performed before initiating IFN therapy, including clinical examination, and measurement of TSH and anti-thyroperoxidase antibodies (TPO Ab). During treatment, a TSH assay every other month appears to be necessary and sufficient.