BACKGROUND: Levels of high-density lipoprotein (HDL) cholesterol are inversely related to cardiovascular risk. Torcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, increases HDL cholesterol levels, but the functional effects associated with this mechanism remain uncertain. METHODS: A total of 1188 patients with coronary disease underwent intravascular ultrasonography. After treatment with atorvastatin to reduce levels of low-density lipoprotein (LDL) cholesterol to less than 100 mg per deciliter (2.59 mmol per liter), patients were randomly assigned to receive either atorvastatin monotherapy or atorvastatin plus 60 mg of torcetrapib daily. After 24 months, disease progression was measured by repeated intravascular ultrasonography in 910 patients (77%). RESULTS: After 24 months, as compared with atorvastatin monotherapy, the effect of torcetrapib-atorvastatin therapy was an approximate 61% relative increase in HDL cholesterol and a 20% relative decrease in LDL cholesterol, reaching a ratio of LDL cholesterol to HDL cholesterol of less than 1.0. Torcetrapib was also associated with an increase in systolic blood pressure of 4.6 mm Hg. The percent atheroma volume (the primary efficacy measure) increased by 0.19% in the atorvastatin-only group and by 0.12% in the torcetrapib-atorvastatin group (P=0.72). A secondary measure, the change in normalized atheroma volume, showed a small favorable effect for torcetrapib (P=0.02), but there was no significant difference in the change in atheroma volume for the most diseased vessel segment. CONCLUSIONS: The CETP inhibitor torcetrapib was associated with a substantial increase in HDL cholesterol and decrease in LDL cholesterol. It was also associated with an increase in blood pressure, and there was no significant decrease in the progression of coronary atherosclerosis. The lack of efficacy may be related to the mechanism of action of this drug class or to molecule-specific adverse effects.