In the present studies, the long term effects of IFN alpha on thyroid function and thyroid autoantibodies were evaluated in 42 patients with chronic viral hepatitis type C treated with IFN alpha for at least 4 months. Before IFN treatment, 41 patients tested were all euthyroid. Five (12%) out of 24 patients tested had positive tests for thyroid autoantibodies. MCHA/TPOAb was detected in all 5 and TGHA/TGAb in 3 out of these 5 patients. Six to 10 x 10(6) units (U) of recombinant or natural IFN alpha were given intramuscularly daily for the first 2 to 4 weeks, followed by 3 to 10 x 10(6) U thrice weekly for the subsequent 14 to 22 weeks. Thyroid dysfunction and/or rises in titers of thyroid autoantibodies were observed in 6 patients during IFN alpha treatment; clinically overt thyroid dysfunctions, destructive thyroiditis and thyrotoxicosis of unidentified etiology, developed in 2 patients 4 to 5 months after start of IFN treatment, subclinical hypothyroidism with a slight increase in serum TSH concentrations but no serum thyroid hormone alternations was observed in 2 patients, and increases in titers of thyroid autoantibodies without thyroid dysfunction were found in 2 patients. Thus, IFN alpha exacerbated thyroid autoimmunity exclusively in all patients with positive tests for thyroid autoantibodies prior to treatment, but did not induce thyroid autoimmunity in thyroid autoantibody-negative patients. These data suggest that the prolonged IFN alpha therapy can lead to exacerbation of thyroid autoimmunity in susceptible (thyroid autoantibody-positive) patients.