The pharmacokinetics of cyclosporine (CSA; 2 mg/kg given iv over a period of 2 h every 12 h) in whole blood, plasma, high-density lipoproteins (HDL), and low-density lipoproteins (LDL) were studied after single (n = 10) and multiple (31 days; n = 6) doses in patients receiving allogeneic bone marrow transplants. Whereas HDL-cholesterol levels decreased significantly, LDL-cholesterol levels increased from day 1 to day 31 of CSA dosing. The mean area under the concentration-time curve and half-life values of CSA in whole blood or total plasma did not differ after single or multiple doses. Greater amounts of CSA were contained in the HDL relative to the LDL fraction over the 24-h period after a single dose; the reverse was found after multiple dosing. Cyclosporine was not detectable in the very LDL fractions. The percentage of total plasma CSA contained in each lipoprotein fraction was independent of the concentration of CSA in total plasma or whole blood. The pharmacokinetics of CSA in the various biologic matrices were not associated with measurements of kidney and liver function. Taken together, the variability of CSA pharmacokinetics previously reported in whole blood or total plasma was also found in lipoprotein fractions. The relative changes in CSA content of lipoproteins may offer an explanation for differences in drug effect with multiple dosing.