Cholesteryl ester transfer protein (CETP) is responsible for the transfer of cholesteryl esters from high-density lipoproteins to apolipoprotein (apo) B–containing lipoproteins in exchange for triglycerides. Inhibition of CETP raises plasma levels of high-density lipoprotein cholesterol but has uncertain effects on atherosclerosis. It has been suggested that CETP may promote the process of reverse cholesterol transport (RCT) (and thus CETP inhibition may inhibit it), but the effect of CETP on RCT is unknown. Mice naturally lack CETP, and in the present studies a gene transfer vector was used to stably express human CETP in different mouse models of lipoprotein metabolism. A validated method to measure RCT from the macrophage through the plasma to the liver and feces was used to assess the effect of CETP expression on RCT. The results indicate that CETP expression, although it reduced high-density lipoprotein cholesterol concentrations, promoted RCT in the setting of effective clearance of apoB-containing lipoproteins; however, it was ineffective in the setting of impaired clearance as a result of deficiency in the low-density lipoprotein receptor. Furthermore, CETP expression normalized RCT in mice deficient in the liver high-density lipoprotein scavenger receptor class B, type I, which is known to have highly defective RCT. The present studies suggest that the CETP pathway may promote RCT and thus be antiatherogenic in the setting of effective clearance of apoB-containing lipoproteins but be proatherogenic in the setting of impaired clearance of apoB-containing lipoproteins. Thus the effectiveness of CETP inhibition as a therapeutic strategy for atherosclerosis may depend in part on the underlying metabolic mileau with regard to the efficiency of apoB-lipoprotein clearance.