AbstractPreviously, we have shown that liposomal amphotericin B (L-AmpB) is less nephrotoxic than and equally as effective as free AmpB as treatment of patients with systemic fungal infections; The mechanism of L-AmpB's enhanced therapeutic index, however, remains unknown. This review discusses AmpB's association with lipoproteins, predominantly high-density lipoproteins (HDL) and the biological relevance of transferring AmpB to HDL. We observed that AmpB was less toxic to pig kidney cells when associated with HDL but still remains toxic when associated with low-density lipoproteins (LDL). AmpB's association with HDL or LDL does not alter its antifungal activity. We further found that these kidney cells express high- and low-affinity LDL receptors but only low-affinity HDL receptors. The reduced renal cytotoxicity of HDL-associated AmpB may be due to its lack of interaction with the renal cells, since they have no HDL receptors. Since AmpB interacts with cholesteryl esters in serum, whose transfer between HDL and LDL is regulated by lipid transfer protein (LTP), we addressed the role of this protein on the distribution of AmpB between HDL and LDL. The addition of LTP altered the lipoprotein distribution of AmpB but not of L-AmpB. Furthermore L-AmpB, but not AmpB (except at 20μg/ml), inhibited the LTP-mediated transfer of cholesterol esters from HDL to LDL. It appears therefore, that the decreased nephrotoxicity associated with L-AmpB administration is related to its predominant distribution to HDL, which is regulated by inhibiting of LTP-mediated cholesterol esters transfer activity.