© 2020 Informa UK Limited, trading as Taylor & Francis Group. Objective: Determine the latent structure of health literacy in persons living with HIV (PLWH) and its association with health management and decision-making. Method: Participants included 220 PLWH and 123 seronegative participants from Southern California and Alabama who completed a battery of well-validated health literacy measures, along with assessments of health management self-efficacy, health-related decision-making, depression, and basic clinical laboratory measures. Results: Exploratory factor analysis in HIV − participants showed that the shared variance between a battery of health literacy measures, including health word reading, verbal comprehension, numeracy, and self-reported problems was best explained by a single factor. Similarly, a confirmatory factor analysis in PLWH also supported a single factor structure, but for a re-specified four-test solution based on the core performance-based measures of health literacy. In analyses adjusting for demographics, PLWH demonstrated significantly lower health literacy composite scores as compared to their HIV − counterparts. Among PLWH, lower health literacy was independently associated with lower self-efficacy for health management and poorer health-related decision-making. Conclusions: Findings suggest that numeracy, word recognition, and verbal comprehension and reasoning comprise a unitary construct of health literacy that is lower in PLWH as compared to seronegatives and is independently associated with important downstream aspects of health management and decision-making.