Research has shown that HIV-related stigma contributes to people living with HIV having a higher risk of mental health disorders. Our study examines the association between enacted HIV-related stigma and symptoms of anxiety and depression among PLWH. We used baseline data from 932 PLWH collected from the Florida Cohort study between 2014 and 2018. The sample was majority 45 + years of age (63.5%), male (66.0%), and Black (58.1%). The majority had previously experienced enacted HIV-related stigma (53.1%). Additionally, 56.6% and 65.2% showed mild to moderate/severe levels of anxiety and depression, respectively. Those who experienced any levels of enacted HIV-related stigma (vs none) had significantly greater odds of mild and moderate/severe levels of anxiety (vs no/minimal) (AOR[CI] 1.54[1.13, 2.10], p = 0.006; AOR[CI] 3.36[2.14, 5.26], p < 0.001, respectively) and depression (AOR[CI] 1.61[1.19, 2.18], p = 0.002; AOR[CI]  3.66[2.32, 5.77], p < 0.001, respectively). Findings suggest a need to evaluate interventions for PLWH to reduce the deleterious effects of enacted HIV-related stigma on mental health.