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Combined antiretroviral therapy (cART) in the treatment of HIV-1 infection confers significant survival benefit and, by immunoreconstitution, has altered the natural history of this life-threatening disease. Metabolic complications of cART include hyperlipidemia, insulin resistance, and lipodystrophy, with resultant increases in risk for type 2 diabetes and cardiovascular disease. These diseases will present new challenges in the management of HIV infection. This article reviews the prevalence of diabetes mellitus and its antecedents in HIV-infected patients treated with cART. It also reviews the current understanding of mechanisms involved in the pathogenesis of type 2 diabetes in cART considering insulin resistance and insulin secretion, both requisites for the development of type 2 diabetes mellitus.