Cyclosporine A (CsA) is a very lipophilic, immunosuppressive peptide that is highly bound (greater than 95%) in plasma. Approximately 50% of the drug is bound to lipoproteins and the remainder to erythrocytes. Neither the therapeutic nor the toxic effects of cyclosporine have been correlated with the free drug concentration. It has been proposed that low-density lipoprotein (LDL) delivers CsA to T-lymphocytes via the LDL receptor pathway, where it then produces its therapeutic effects. We have found that our patients chronically treated with cyclosporine carry as much or more CsA in very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and high-density lipoprotein (HDL) as they do in LDL. In addition, as previously reported, those patients with high VLDL carried the major portion of CsA in their VLDL subfraction. Moreover, the triglyceride-rich lipoproteins (VLDL and IDL) were found to contain much more CsA per mg of lipid than either HDL or LDL. An acute drug challenge led to the same CsA distribution as that seen in the chronically treated patients. "In vitro" incubations of lipoproteins containing CsA with lipoproteins from untreated individuals demonstrated a different relative affinity of CsA for the various lipoproteins than would be predicted from the plasma distribution: LDL greater than VLDL greater than HDL. We propose that the plasma distribution of CsA is determined by factors other than simple diffusion between the lipoprotein particles. Possible mechanisms would include (a) plasma factors that augment or inhibit CsA transfer or (b) metabolic processing of the lipoproteins that move CsA from one lipoprotein to another.