The proportion of human immunodeficiency virus (HIV)-infected patients aged 50 and older has greatly increased since the beginning of the epidemic, particularly since 1996, when combination antiretroviral therapy became available. By 2015, 50% of HIV-infected individuals in the United States are likely to be aged 50 and older. The rate of progression of untreated HIV disease, response to therapy, and complicating effects of comorbidities differ in older and younger patients. Older untreated patients with HIV demonstrate faster rates of CD4+ cell loss and more rapid progression to acquired immunodeficiency syndrome (AIDS) and death than younger individuals. Synergistic deleterious effects of chronic immune activation on the course of HIV infection with the immune senescence of aging may promote this accelerated course. Despite the increasing prevalence in older patients and cost-effectiveness analyses that favor HIV testing, older patients are less likely to be routinely evaluated for HIV infection. Consequently, when diagnosed, older patients have more-advanced disease than do younger patients and, upon presentation with AIDS-defining conditions, are less likely to receive timely appropriate therapy. The treatment of older HIV-infected patients is complicated by preexisting comorbid conditions, including cardiovascular, hepatic, and metabolic complications, which in turn may be exacerbated by the effects of HIV infection per se, modest immunodeficiency (i.e., at CD4+ counts >350 cells/μL), and the metabolic and other adverse effects of combination antiretroviral therapy. Nevertheless, older patients derive substantial benefit from combination antiretroviral therapy despite having less of an immunological response than expected given their adherence to therapy and excellent virological responses.