© This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Objective Requiring only 10–15 minutes to complete, the UCSD Performance-Based Skills Assessment (UPSA-B) has high clinical utility as a brief measure of functional capacity. This study aimed to validate the UPSA-B in adults living with HIV/AIDS (HIV+), and identify whether the UPSA-B can be used as an indicator of functional dependence in this population. Method One hundred and three HIV+ adults and 91 HIV- adults completed a comprehensive neuropsychological and neuromedical battery, including a self-report measure of functional status (IADL Dependence vs. IADL Independence), an objective measure of functional capacity (UPSA-B), and a self-report measure of mood states including a subscale related to cognitive difficulties (Profile of Mood States [POMS]-Confusion/Bewilderment subscale). Results HIV+ participants had significantly lower UPSA-B scores than their HIV- counterparts (p = 0.02), although this fell to a trend (p = 0.08) when including covariates. Among the HIV+ group, higher UPSA-B scores were related to better neuropsychological ability, but unrelated to self-reported functional independence. Conversely, UPSA-B scores were unrelated to participant-reported cognitive difficulties on the POMS Confusion/Bewilderment subscale. An ROC curve was generated to determine the optimal UPSA-B value for discriminating between normal neuropsychological functioning versus neuropsychological impairment, with results indicating an optimal cutoff of 79. The UPSA-B identified HIV+ persons with cognitive impairment with 70.9% accuracy. Conclusions The UPSA-B was able to differentiate neuropsychological impairment from no impairment among HIV+ participants and holds promise as a clinical screening tool in this population. However, indicators of functional disability among adults living with HIV is still not well understood and is likely multifactorial in nature. These data highlight the complex interplay between objective functional capacity, neurocognitive ability, subjective cognitive symptoms, and functional dependence.