Although the association of lipophilic drugs with plasma lipoproteins has not been fully characterized, there are several reports of lipoprotein association being influential in pharmacokinetic and pharmacodynamic profiles of important therapeutic agents. The current studies utilized a series of aliphatic esters of halofantrine to evaluate the role of several physicochemical properties on the interaction of the different compounds with plasma lipoproteins. Density gradient ultracentrifugation techniques were employed to determine drug association in triglyceride rich (TRL), low-density (LDL) and high-density lipoproteins (HDL), under both fasted and post-prandial conditions. Compound solubility in medium or long chain triglycerides was a useful indicator of the extent of drug-lipoprotein association, particularly for the triglyceride rich lipoproteins (chylomicrons and very low-density lipoproteins). This is likely a function of the compounds being solubilized within the apolar (triglyceride and cholesterol ester) lipid core. However, molecular size also played an important role in determining lipoprotein distribution, particularly for association with the more protein abundant lipoproteins, such as HDL. Lipoprotein association of Hf analogues containing longer unsaturated esters was best correlated with total lipoprotein surface area rather than with lipoprotein core lipid volumes.