In clinical practice, combination antiretroviral therapy is frequently complicated by adverse reactions and drug-related toxicities. The incidence, presentation, differential diagnosis, and management of the most frequent and severe of these complications are discussed. The recently described spectrum of metabolic complications, including hyperlipidemia, fat redistribution, and lactic acidosis, are covered in detail. The management of nephrotoxicity, pancreatitis, bone marrow suppression, peripheral neuropathy, and hypersensitivity reactions related to antiretroviral therapy is also discussed.