People over age 50 living with HIV experience frailty including functional declines and illnesses usually attributed to aging, more frequently and ten years earlier than people without HIV As the number of people living with HIV over age 50 is expected to triple by the year2040, those experiencing early frailty will continue to grow. This review synthesizes the known correlates and contributors to musculoskeletal frailty in people living with HIV. A conceptual model of musculoskeletal frailty in HIV that outlines chronic inflammation, altered energy metabolism, immune activation, and endocrine alterations as mechanisms associated with frailty development is presented. Additionally, the potential ability of aerobic exercise to modify the risk of frailty is highlighted as an important intervention.