STUDY OBJECTIVE: To determine the safety and efficacy of intravenous cyclophosphamide for patients with idiopathic pulmonary fibrosis. DESIGN: Nonrandomized, open-labeled study of efficacy in symptomatic patients. SETTING: Patients were treated as outpatients in a referral clinic. PATIENTS: All patients had idiopathic pulmonary fibrosis with symptoms of dyspnea on exertion. Patients had either worsening disease or contraindication to corticosteroids. INTERVENTION: Thirty-three patients were treated with intravenous cyclophosphamide every two weeks. Initial dosage was 500 mg, and the dose was escalated provided the total white blood cell count remained > 3,000 cells per cubic millimeter. The maximum dose administered was 1,000 to 1,800 mg of cyclophosphamide. Corticosteroid therapy was tapered as tolerated by the patient. MEASUREMENTS AND RESULTS: Patients were treated for at least six months or until death. For the 33 patients, 18-month probability of survival was > 50 percent. For those patients surviving six months, there was a significant rise in the vital capacity (from 1.6 +/- .61 L [mean +/- SD] to 1.8 +/- .52 L, p < 0.01) which persisted for at least 18 months of treatment. This was associated with a significant fall in the average prednisone dosage from 32 +/- 13.0 mg/day to 4 +/- 10.4 mg/day (p < 0.01) by 12 months. Only one patient required hospitalization for possible drug-related toxic reaction. CONCLUSIONS: Intermittent, intravenous cyclophosphamide therapy was associated with improved pulmonary function and reduced corticosteroid dosage in patients with idiopathic pulmonary fibrosis who survived at least six months after institution of therapy.