Frailty is a clinical syndrome initially characterized in geriatric populations with a hallmark of age-related declines in physiologic reserve and function and increased vulnerability to adverse health outcomes. Recently, frailty has increasingly been recognized as a common and important HIV-associated non-AIDS (HANA) condition. This article provides an overview of our current understanding of frailty and its phenotypic characteristics and evidence that they are related to aging and to chronic inflammation that is associated with aging and also with long-term treated HIV infection. The etiology of this chronic inflammation is unknown but we discuss evidence linking it to persistent infection with cytomegalovirus in both geriatric populations and people living with HIV infection.