To investigate the variability in the unbound fraction (fU) of cyclosporine in recipients of heart, heart-lung, and lung transplantation, cyclosporine fUwas derterminedex vivoin plasma by equilibrium dialysis. In a retrospective study, 260 samples of plasma (one to seven per patient) were obtained from 89 heart (86%), lung (9%), and heart-lung (5%) transplant patients. The unbound fraction (×100) of cyclosporine ranged from 0.52% to 3.94%, with an overall mean of 1.53% ± 0.375% (SD). The mean percentage unbound for individual patients ranged from 0.71% to 1.98%, giving a 2.8-fold interpatient variation. In heart transplant recipients (66 patients), the values of fUwere significantly lower (p< 0.01) during more severe rejection episodes, which required antirejection treatment (endomycardial biopsy result of grade 3a and higher) than in the absence of rejection (grade 0) or during grade 1a rejections. The value of fUdid not vary with organ transplanted (p= 0.35) or etiology of organ failure (p= 0.32). Cyclosporine fUwas negatively correlated with the age of the patient (r= -0.18,p< 0.05). Correlations were not observed between fUand blood biochemical and cytologic indices. However, fUwas significantly lower (p< 0.01) in hypercholesterolemic transplant recipients (1.37 ± 0.52%) than in normocholesterolemic patients (1.60 ± 0.63%). Administration of simvastatin resulted in a significant increase in the mean fUfrom 1.40 ± 0.09%) to 1.82 ± 0.13% (pairedttest, n = 13;p< 0.01). In patients who received ketoconazole, fUwas not different from controls. These findings suggest that the level of cyclosporine fUmay be an important determinant immunosuppressive activity of cyclosporine. Moreover, the variation in fUcould be strongly related to the concentration of serum lipoproteins; interpretation of the results of cyclosporine monitoring thus requires consideration of the lipidemic status of the patient.