A 54-year-old male patient was admitted to Osaka University Medical School Hospital for interferon treatment for chronic hepatitis C and the daily administration of recombinant interferon-alpha 2a started at the dose of 9 megaunits per day. Fourteen days later, moderate right pleural effusion was detected by abdominal magnetic resonance imaging study. He had experienced no symptom to suggest pleural effusion or any pulmonary lesions during interferon treatment. The pleural fluid was serous, showing the character of slightly bloody, turbid and positive Rivalta test, and the levels of lactic dehydrogenase and adenosine deaminase were not elevated. His serum titer of anti-nuclear antibody increased to 80 in homogenous staining, but anti-DNA antibody and anti-liver kidney microsome-1 antibody remained negative. Other laboratory tests or physical findings could not satisfy the criteria of any autoimmune diseases, such as systemic lupus erythematosus. After discontinuation of interferon administration, his pleural effusion resolved gradually and disappeared completely by use of no specific drugs. This is the first case that pleural effusion developed during interferon administration without any other clinical signs indicating autoimmune diseases. The increase of serum titer of anti-nuclear antibody prompted us to elucidate that pleuritis might be induced by immunological activation of interferon.