Lipodystrophy is an increasingly recognized complication of antiretroviral therapy for human immunodeficiency virus (HIV) infection. This syndrome encompasses both fat accumulation and wasting, which may be accompanied by metabolic derangements in glucose and lipid metabolism. While the precise mechanism of its development is not fully understood, lipodystrophy may represent chronic mitochondrial toxicity due to antiretroviral therapy and/or chronic HIV infection. Treatment of this condition has proven difficult, prompting research into agents that promote fat metabolism and mitochondrial function. L-carnitine is a nonessential micronutrient that regulates fatty acid transport into the mitochondrial matrix for metabolism via beta-oxidation. HIV-infected individuals on antiretroviral therapy may become deficient in this cofactor, limiting mitochondrial fat metabolism. While studies have shown some benefit for carnitine supplementation in cardiovascular disease, mitochondrial myopathies, and possibly male infertility, the data for its use in HIV-infected individuals are limited. Given its known physiologic function and the hypothesized mitochondrial basis for lipodystrophy, carnitine supplementation for this antiretroviral toxicity is reviewed. The available data from several small studies are inconclusive, although further research into this promising agent is warranted.