The CHICAGO study (Carotid Intima-Media Thickness in Atherosclerosis Using Pioglitazone) tested the hypothesis that pioglitazone would have a beneficial effect for reducing CIMT progression, compared with glimepiride. Treatment with pioglitazone produced improvement in several parameters, such as systolic blood pressure and lipid levels, including a 14% increase in HDL cholesterol, and reduced CIMT progression, compared with glimepiride. However, only the beneficial effect on HDL cholesterol predicted its beneficial effect for reducing CIMT progression. The following review examines data from additional studies evaluating how pioglitazone and HDL levels modify cardiovascular risk.