Objective: Although the decline in the pulmonary transfer factor (TLCO) following heart transplantation is well documented, the causes and mechanisms of this decline remain unknown. The aim of this study was to determine the relative contribution of each of TLCO components (the diffusing capacity of the alveolar-capillary membrane (D-M), the pulmonary capillary blood volume (V-C) and haemoglobin concentration) to TLCO reduction in heart transplant recipients. Methods: TLCO and its components were measured in 75 heart transplant recipients (mean age 48 years, range 19-61) between 6 weeks and 36 months after transplantation using the Roughton and Forster method and the single-breath technique. Results were compared with data from 38 heart transplant candidates (mean age 51 years, range 34-61) and 26 normal subjects (mean age 47 years, range 27-62). Results: The mean percentage predicted TLCO was reduced in recipients compared to candidates (56.9 and 69.9%, respectively, P < 0.001) and both were lower than normal controls (97.7%, P(0.001). The mean percent predicted V-C was also reduced in recipients compared to candidates (52.8% vs. 80.2 (4.2)%, P < 0.001) which was also lower than normal subjects (102%, P < 0.001). D-M was equally reduced in recipients and candidates (77.7 and 81.4%, respectively, P = 0.48) compared to normal subjects (100.0%, P < 0.001). Correction for haemoglobin concentration increased TLCO in recipients to 63.5% (P < 0.001), but it remained lower than haemoglobin-corrected TLCO in candidates (71.1%, P < 0.001). in recipients, the intra-capillary resistance (1/theta V-C) formed 60% of the total resistance to CO transfer (1/TLCO) compared to 50% in candidates and normal subjects. Conclusions: TLCO decline following heart transplantation is due to an increase in the intra-capillary resistance, and this appears to be due to a combination of anaemia and reduced pulmonary capillary blood volume, with the diffusing capacity of the alveolar-capillary membrane remaining unchanged. (C) 2000 Elsevier Science B.V. All rights reserved.