We report three cases of chronic hepatitis C (HC) with pneumonitis, suspected to be caused by natural and recombinant interferon (INF) alfa treatments. The patients were administered INF through intramuscular injection. All three patients developed acute respiratory failure (PaO2 < or = 60 mm Hg) with bilateral lung infiltration. One of the patient's condition improved after the cessation of INF treatment, without any other therapy. The other two patients were administered corticosteroids, and one patient's condition improved, while in the other patient the pneumonitis persisted, even after a high dose of corticosteroids. To our knowledge, these three cases are the first report of pneumonitis associated with INF alfa in patients with chronic HC.