© 2020 The Author(s) 2020. Published by Oxford University Press. All rights reserved. Objective: People living with HIV (PLWH) are at higher risk for poorer neurocognitive functioning and health literacy than uninfected persons, which are associated with worse medical outcomes. Aging research suggests that the effect of neurocognitive functioning on health outcomes may be more pronounced in those with low health literacy. We aimed to determine whether low health literacy might amplify the adverse effects of neurocognitive functioning on treatment management outcomes in 171 PLWH aged 40+. Method: In this cross-sectional, observational study, participants completed a well-validated battery of neurocognitive, health literacy, and treatment management measures. A binary health literacy variable (low vs. adequate) was determined via established cut points on the well-validated health literacy tests. Treatment management outcomes included biomarkers of HIV (i.e., CD4 counts and viral load), self-management of HIV disease (i.e., self-reported medication adherence and self-efficacy for HIV disease management), and performance-based health-related decision-making. Results: Forty-seven percent of the sample met the criteria for low health literacy. Multivariable regressions adjusting for clinicodemographic (e.g., race, socioeconomic status) covariates revealed significant interactions for self-efficacy for HIV disease management and health-related decision-making, such that neurocognitive functioning was associated with these outcomes among those with low, but not adequate health literacy. Conclusions: Findings suggest that low health literacy may increase the vulnerability of PLWH to the adverse effects of neurocognitive impairment on health outcomes, or conversely that adequate health literacy may provide a buffer against the health risks associated neurocognitive impairment. Interventions targeting health literacy in PLWH may mitigate the effects of neurocognitive impairment on health outcomes.