Despite the availability of highly active antiretroviral therapy and the resulting reduction in severe anemia associated with HIV infection, epoetin alfa has continued to play an important role in the management of HIV-infected patients. Mild-to-moderate anemia remains common, and its correction with epoetin alfa has resulted in significant improvements in quality of life, physical functioning, and possibly prolongation of survival. New research has demonstrated that epoetin alfa may have therapeutic potential beyond its ability to stimulate erythropoiesis due to its neuroprotective and antiapoptotic properties. Current and future research will further clarify the role of epoetin alfa in the clinical management of the HIV-infected population.