Clinical heart-lung transplantation (HLT) began at Stanford University (Stanford, CA) in 1981, and since then, over 40 HLTs have been performed. There is now a worldwide total of 250 HLTs. While much of the pathology that occurs in patients receiving an HLT is similar to that which develops in patients with other transplanted organ systems, these patients also develop unique clinical complications and pathologic processes that deserve emphasis. We report the autopsy findings of 20 HLT recipients, of whom 12 died in hospital one day to 4 months post-HLT. A major contributing factor in five of these postoperative deaths was pleural hemorrhage from adhesions due to prior chest surgery. Overwhelming viral and fungal infections accounted for six deaths. The seventh patient died as a result of adult respiratory distress syndrome (ARDS). Two patients showed histologic evidence of the reimplantation response. Six long-term survivors died (mean survival, 22 months) with obliterative bronchiolitis (OB). In four patients, OB was the immediate cause of death, while one patient died of an intercurrent myocardial infarct, and the other patient died of complications from an appendectomy. Two long-term survivors died without OB, one of iatrogenic causes at 63 months and the second due to unexplained ARDS at 52 months. Both patients without OB had virtually normal underlying pulmonary parenchyma. All of the long-term survivors had either coronary arterial or pulmonary vascular intimal sclerosis, and renal lesions attributable to cyclosporine A toxicity. Although histologic features of mild acute pulmonary and cardiac rejection were observed in four patients overall, these did not contribute to the cause of death in any case. Although OB is a major threat to its success, HLT is a viable option for patients with endstage pulmonary disease.