This study sought to determine the effects of HIV-associated neurocognitive disorders (HAND) on health literacy, which encompasses the ability to access, understand, appraise, and apply health-related information. Participants included 56 HIV seropositive individuals, 24 of whom met Frascati criteria for HAND, and 24 seronegative subjects who were comparable on age, education, ethnicity, and oral word reading. Each participant was administered a brief battery of well-validated measures of health literacy, including the Expanded Numeracy Scale (ENS), Newest Vital Sign (NVS), Rapid Estimate of Adult Literacy in Medicine (REALM), and Brief Health Literacy Screen (BHLS). Results revealed significant omnibus differences on the ENS and NVS, which were driven by poorer performance in the HAND group. There were no significant differences on the REALM or the BHLS by HAND status. Among individuals with HAND, lower scores on the NVS were associated with greater severity of neurocognitive dysfunction (e.g., working memory and verbal fluency) and self-reported dependence in activities of daily living. These preliminary findings suggest that HAND hinders both fundamental (i.e., basic knowledge, such as numeracy) and critical (i.e., comprehension and application of healthcare information) health literacy capacities, and therefore may be an important factor in the prevalence of health illiteracy. Health literacy-focused intervention may play an important role in the treatment and health trajectories among persons living with HIV infection.