Chronic rejection is the major cause of death of long-term survivors of heart-lung transplantation. Of our 61 patients who have received heart-lung transplants, 29 have been followed up for a year or longer. Seven patients had clinical evidence of chronic rejection within 15 months of transplantations of these seven, four died with postmortem confirmation of extensive obliterative bronchiolitis, interstitial and pleural fibrosis, and vascular sclerosis in the heart and lungs. All seven patients had evidence on transbronchial biopsy specimens of submucosal fibrosis and vascular sclerosis. Twelve of our remaining patients have shown similar areas of lung fibrosis on transbronchial biopsy specimens, and the other 10 are well and without fibrosis seen on transbronchial biopsy specimens. Studies of the 201 biopsy specimens obtained from 29 patients confirmed rejection on 130 occasions, with more frequent, more persistent, and more severe rejection in the chronic-rejection group than in the without-fibrosis or lung-fibrosis group. Opportunistic infections resulted in pneumonia on 19 occasions, and these were most commonly found in patients with lung fibrosis. We conclude that chronic lung rejection is the likely outcome in patients with early, poorly controlled, severe rejection.