Bilateral symmetrical polyarthritis occurred in three patients (2 males and 1 female), with no previous history of inflammatory rheumatologic disease, given alpha-interferon for 1 1/2, 7, and 10 months as treatment of chronic non A-non B hepatitis, myelofibrosis, and thrombocytopenia with myeloproliferative disorder, respectively. Joint manifestations developed 1 1/2, 3, and 10 months after initiation of alpha-interferon in a dosage of 3.10(6) U three times a week, 4.5.10(6) U per day, and 8.10(6) U three times a week. Polyarthritis persisted following withdrawal of alpha-interferon in the two last patients of whom one had rheumatoid nodules and positive rheumatoid serology and the other had scleritis, exanthema, and negative rheumatoid serology. Erosive rheumatoid arthritis was diagnosed after 28 months and 12 months, respectively, in two patients who required systemic corticosteroids with antimalarials (1 case) or azathioprine after failure of methotrexate (one case). Follow-up in the third case (12 months) is too short to allow differentiation of systemic lupus erythematosus (ANA: 1/1500 H with anti-DNA antibodies 58 U/ml) and chronic autoimmune hepatitis. Reports of chronic inflammatory rheumatologic disease during alpha interferon therapy are exceedingly few in number. In the cases reported herein, alpha-interferon may have either triggered or revealed the joint disease. To prevent occurrence of this complication, exclusion from alpha-interferon therapy of patients with autoantibodies or a positive history for clinical evidence of immune dysfunction may be considered.