Non-AIDS morbidity and mortality are increasingly common in the HIV-infected population. Chronic inflammation and immunosenescence result in early onset of conditions associated with aging, including atherosclerosis and frailty. Risk for non-AIDS-related morbidity is also related to the metabolic effects of antiretroviral therapy and the increased prevalence of traditional cardiovascular and other risk factors in the HIV-infected population. Risk reduction is centered on maintaining full viral suppression and aggressively implementing measures to reduce standard modifiable risk factors. This article summarizes a presentation by Edgar Turner Overton, MD, at the IAS-USA continuing education program held in New York, New York, in October 2013.