Dyslipidemia and insulin resistance occur in a large proportion of HIV-infected patients treated with highly active antiretroviral therapy (HAART); anthropomorphic changes, such as lipoatrophy and central obesity, occur in a subset of patients. This cluster of clinical features, which is termed HIV lipodystrophy, places patients at increased risk for cardiovascular disease. Currently, there is no consensus on the appropriate therapy for the management of HIV lipodystrophy for which the underlying defects are enhanced lipolysis, impaired fat oxidation, increased hepatic VLDL-triglyceride synthesis and secretion, and impaired disposal of intestinally-derived lipoprotein-triglycerides. We describe the design of a randomized, placebo-controlled trial to compare the effects of usual care to diet, exercise and lipid-lowering drugs on lipid profiles of patients with HIV lipodystrophy. The trial will randomize 200 patients into five groups. Outcomes of usual care, diet and exercise alone or in combination with niacin, fenofibrate or both medications will be compared after six months. Unique aspects of the design include an interactive Internet Diet Management system to increase ATP-III recommended dietary compliance for metabolic syndrome, and a supervised program of aerobic and resistance exercises. The study is powered to detect a 20% decrease in triglycerides with the lifestyle intervention and an additional 20% improvement with the addition of niacin and/or fenofibrate. Secondary outcomes include assessment of lipid profile changes, LDL and HDL particle size, plasma cholesterol ester transport protein activity, visceral and subcutaneous fat distribution, glucose tolerance, insulin resistance, and leptin and adiponectin levels.