Insulin resistance is increasingly recognized among HIV-infected patients with fat redistribution (lipodystrophy) who are receiving highly active antiretroviral therapy. The mechanisms of insulin resistance in this population remain unknown, but could relate to a decrease in glucose transport caused by the direct effects of certain antiretroviral agents, such as the protease inhibitors, or to the effects of severe fat redistribution, including subcutaneous fat loss and increased visceral adiposity. Insulin resistance in patients with HIV lipodystrophy is associated with hyperlipidemia and impaired fibrinolysis, and might increase the risk of cardiovascular disease (CVD). Furthermore, insulin-sensitizing agents might improve insulin resistance and reduce the risk of CVD in this population.