Impairment of pulmonary diffusion (KCO) is frequently seen in patients following orthotopic heart transplantation (HTX). To assess potential histomorphological pulmonary causes of KCO abnormalities, we evaluated tissue samples from 73 patients who succumbed after HTX in the presence of KCO abnormalities, excluding those with infectious or primary pulmonary causes of death. In 97% of subjects, we observed considerable histomorphological changes in interstitial or vascular tissue or both. In 32% of samples, interstitial changes (eg, cell proliferation or fibrosis) were accompanied by vascular abnormalities, whereas more than two-thirds of the patients showed alterations in one of the two conditions. Hemosiderin-laden macrophages were observed in 48% of subjects. The mean alveolar-capillary wall thickness was significantly increased to 9.9 +/- 4.2 mum. The time of survival after HTX was not correlated with the incidence of pathological findings. The described vascular and interstitial pulmonary changes as well as the increased membrane thickness may cause the persistent impairment of KCO after HTX.