Previous studies have demonstrated that mouse peritoneal macrophages take up low-density lipoproteins (LDL) which have been chemically modified by the acetylation of lysine residues (Ac-LDL). This uptake is mediated through a specific receptor known as the scavenger receptor. Ac-LDL therefore appear to have excellent potential for antiinfectious drug targeting. We have developed a new method to incorporate ketoconazole-oleate, a lipophilic derivative of ketoconazole, into Ac-LDL. The method involves solubilization of LDL in the presence of Na deoxycholate, the addition of a micellar solution of the drug to be incorporated, and the subsequent removal of the detergent leading to the formation of reconstituted LDL (referred to as LDL-KOL). The LDL-KOL contain 200 drug molecules per LDL particle and compete for the binding of native 125I-LDL on human skin fibroblast monolayers. Furthermore, reconstituted LDL-KOL are indistinguishable from native LDL with regard to lipid composition and electrophoretic mobility. LDL-KOL, when acetylated, are recognized by the scavenger receptor. Acetylated LDL-KOL show antileishmanial activity when tested on infected macrophages. The activity appears to be mediated through the scavenger-cell pathway, as LDL-KOL are inactive under the same conditions. Moreover, acetylated LDL-KOL are selectively accumulated within infected macrophages rather than in normal cells. This may be of value in the treatment of intracellular infections.