We describe a patient who developed progressive inflammatory polyarthritis after treatment with interferon-alpha (IFN-alpha) for chronic hepatitis C infection. Rechallenge with the drug caused worsening of the arthritis, but withdrawal did not result in remission. Preexisting autoantibodies and HLA-DR4 were detected in this serum and are thought to be relevant in the etiology of IFN-alpha associated autoimmune disease.