A 76-year-old woman presented with non-productive cough and progressive dyspnea, and was admitted to Oita Medical University Hospital. Arterial blood gas values obtained on admission indicated severe hypoxemia. Chest roentgenograms and computed tomography disclosed diffuse interstitial infiltrates in both lungs. Transbronchial lung biopsy specimens demonstrated thickened alveolar walls with lymphocyte infiltration and swollen type II pneumocyte proliferation. Eosinophils were observed mainly around bronchioles. For approximately 6 months prior to hospitalization, the patient had been given misoprostol, sodium aurothiomalate, prednisolone, and loxoprofen sodium for the treatment of rheumatoid arthritis. Based on the clinical history and findings, drug-induced interstitial pneumonia was suspected. All medications were discontinued, and the patient was then placed on corticosteroids. After treatment, arterial blood gas values improved and the findings on chest roentgenograms cleared up. Positive lymphocyte stimulation tests and positive dermal reaction patch tests implicated misoprostol as an etiologic factor in the patient's interstitial pneumonia. High serum levels of KL-6 and cytokeratin subunit 19 fragment had been detected on admission. These values returned to normal after the interstitial infiltrates had disappeared. To our knowledge, this is the first reported case of misoprostol-induced interstitial pneumonia.