Background:Chronic HIV disease is associated with neurocognitive impairment and age-related conditions such as frailty.Objective:To determine whether regional brain volumetric changes correlate with frailty parameters in older (≥ 40 years) HIV+ patients on stable combination antiretroviral therapy.Method:Thirty-five HIV-infected participants in the Hawaii Aging with HIV Cohort - Cardiovascular Disease study underwent T1-weighted brain magnetic resonance imaging, frailty assessment and neuropsychological testing. Five physical frailty traits were assessed: low physical activity; exhaustion; unintentional weight loss; weak hand grip strength; slow walking speed. Linear regression quantified cross-sectional relationships of 12 brain regions to walking times and hand grip strength.Results:Participants were 50.6 ± 6.8 years old and 77% had undetectable plasma viral load. One subject was frail (possessing ≥ 3 frailty traits); 23% were pre-frail (1–2 frailty traits) and had worse composite learning and memory z-scores than did non-frail individuals (p=0.06). Pre-frail or frail subjects had reduced hand grip strength relative to the non-frail group (p=0.001). Longer walking times (slower gait) related independently to lower volumes of cerebellar white matter (ppp< 0.05, β=0.4). Caudate volume was negatively associated with grip strength (pConclusion:Volumetric changes in cerebellar white matter and subcortical gray matter, brain regions involved in motor control and cognition, may be connected to frailty development in well-controlled HIV. Gait speed is particularly sensitive to white matter alterations and should be investigated as a predictor of frailty and brain atrophy in chronically infected patients.