Objective: To determine the impact of nutritional (selenium) chemoprevention on levels of psychological burden (anxiety, depression, and mood state) in HIV/AIDS. Method: A randomized, double-blind, placebo-controlled selenium therapy (200 mug/day) trial was conducted in HIV+ drug users from 1998-2000. Psychosocial measures (STAI-State and Trait anxiety, BDI-depression, and POMS- mood state), clinical status (CD4 cell count, viral load), and plasma selenium levels were determined at baseline and compared with measurements obtained at the 12-month evaluation in 63 participants (32 men, 31 women). Results: The majority of the study participants reported elevated levels of both State (68%) and Trait (70%) anxiety. Approximately 25% reported overall mood distress (POMS > 60) and moderate depression (BDI > 20). Psychological burden was not influenced by current drug use, antiretroviral treatment, or viral load. At the 12-month evaluation, participants who received selenium reported increased vigor (p = 0.004) and had less anxiety (State, p = 0.05 and Trait, p = 0.02), compared to the placebo-treated individuals. No apparent selenium-related affect on depression or distress was observed. The risk for state anxiety was almost four times higher, and nearly nine times greater for trait anxiety in the placebo-treated group, controlling for antiretroviral therapy, CD4 cell decline (> 50 cells) and years of education. Conclusions: Selenium therapy may be a beneficial treatment to decrease anxiety in HIV+ drug users who exhibit a high prevalence of psychological burden.