ABSTRACTThis analysis examined the relationships between HIV-related stigma, depression, and anxiety in rural and urban sites. Participants were HIV-positive urban (n = 100) and rural (n = 100) adult residents of a US southern state, drawn from a sample for a larger international study of self-esteem and self-compassion. Measures included demographic and health information, the HIV Stigma Scale, the Center for Epidemiology Studies Depression Scale (CES-D), and the Symptom Checklist 90 Revised (SCL-R-90) anxiety scale. Independent sample t-tests showed no significant differences between urban/rural groups on measures of HIV-related stigma, anxiety, or depression, except that rural participants reported greater disclosure concerns (t = 2.11, df = 196, p = .036). Both groups indicated high levels of depression and anxiety relative to published norms and clinically relevant cut-off scores. Hierarchical regression analyses were conducted for the HIV Stigma Scale including its four subscales and total stigma scores. Block 1 (control) contained health and demographic variables known to predict HIV-related stigma. Block 2 included the CES-D and the SCL-R-90, and Block 3 was urban/rural location. Mental health symptom scores contributed a significant amount to explained variance in total stigma scores (5.5%, FΔ = 6.020, p < .01), personalized stigma (4.8%, FΔ = 5.035, p < .01), negative self-image (9.7%, FΔ = 12.289, p < .001), and concern with public attitudes (4.9%, FΔ = 5.228, p < .01), but not disclosure concerns. Urban/rural location made significant additional contributions to the variance for total stigma (1.7%, FΔ = 3.899, p < .05), disclosure concerns (2.6%, FΔ = 5.446, p < .05), and concern with public attitudes (1.9%, FΔ = 4.169, p < .05) but not personalized stigma or negative self-image. Depression scores consistently and significantly predicted perceived stigma total and subscale scores. Findings suggest that mental health symptoms and urban/rural location play important roles in perceived stigma, and treatment implications are presented.