Antiretroviral therapy for HIV restores immune function, controls viral replication, decreases opportunistic infections, and extends lifespan to near-normal for infected individuals. However, successful HIV therapy has been accompanied by the emergence of treatment-related complications, with an impact not yet fully understood. This article reviews six common complications of antiretroviral therapy, including hyperlactatemia/lactic acidosis, hypersensitivity reactions, abnormal glucose metabolism, dyslipidemia, body composition changes, and cardiovascular disease. A comprehensive approach to management of antiretroviral-related complications includes awareness of (1) risk factors for adverse reactions, (2) clinical syndromes suggestive of an evolving complication, and (3) evidence-based monitoring and treatment strategies. Fluency in options for preventing and managing complications can provide maximal opportunity to balance treatment effects with quality of life.