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Summary: The clinical usefulness of cyclosporine is hampered by doselimiting toxicities to the kidney that are not predicted by drug levels in serum or whole blood. Because of its lipophilic nature, circulating plasma lipoproteins may play a role in drug disposition. This study characterized the pharmacokinetic parameters of a single 2-mg/kg i.v. infusion of cyclosporine in the whole blood, plasma, high-density (HDL), low-density (LDL), and very low-density (VLDL) lipoprotein fractions of nine patients before bone marrow transplantation. The dose- and protein-corrected area under the concentration-time curve in whole blood; plasma; and HDL, LDL, and VLDL compartments were 44.6/Pm 11.3, 19.2 /Pm 2.4; 33.6 /Pm 12.3, 49.0 /Pm 19.9, and 17.5 /Pm 9.0 ng h/ml, respectively. The mean half-life of the drug from the VLDL fraction was significantly less than from the other biologic fluids. The systemic clearance rate of cyclosporine was greater in the total plasma or VLDL fractions compared with whole blood and the HDL and LDL fractions. The HDL-cyclosporine clearance inversely correlated with the serum creatinine (r = −0.76; p < 0.05) and total bilirubin levels (r = −0.76; p < 0.05). The plasma half-life and volume of distribution directly correlated with fasting HDL cholesterol levels (r = 0.94 and 0.99; p < 0.01). Correlations between pharmacokinetic parameters and lipid fractions suggest a role of lipids in the distribution of cyclosporine. These data may be useful in the development of guidelines for therapeutic drug monitoring of cyclosporine in the transplantation population.