Interstitial pneumonia is a major determinant of early and late morbidity and mortality following bone marrow transplantation. Among 952 patients receiving allogeneic marrow grafts in Seattle, 35% developed interstitial pneumonia within 100 days of transplant. Development of early cytomegalovirus (CMV) or idiopathic interstitial pneumonia was infrequent in patients with aplastic anemia prepared only with cyclophosphamide. Use of total body irradiation (TBI) in the transplant preparation, increasing patient age, pretransplant seropositivity for CMV antibody and post-transplant development of graft-versus-host disease (GVHD) all increased the risk of CMV pneumonia. Late interstitial pneumonia was studied in patients with chronic GVHD. Among 198 patients with extensive chronic GVHD, 31 episodes of interstitial pneumonia (seven idiopathic, six CMV, six pneumocystis, five miscellaneous and four unknown causes, and three varicella-zoster) were observed 3-24 months after transplant. In untreated patients with chronic GVHD, 15% developed late interstitial pneumonia. Patients with chronic GVHD who received prednisone +/- azathioprine as immunosuppressive therapy and trimethoprim sulfamethoxazole for infection prophylaxis had an 8% incidence of interstitial pneumonia. Patients with chronic GVHD given immunosuppressive treatment without trimethoprim sulfamethoxazole prophylaxis had a 28% incidence of interstitial pneumonia. Trimethoprim sulfamethoxazole significantly reduced the incidence of late interstitial pneumonia in patients with chronic GVHD (p = 0.001).