Objective: Decision-making involves fronto-striatal brain areas that are particularly vulnerable to the effects of HIV infection. Some studies report impaired decision-making in people with HIV/AIDS with past or present addictions and/or accompanying HIV-associated neurocognitive disorders (HAND). The authors investigated risk-based decision-making in HIV/AIDS, separating individuals with or without accompanying HAND. Method: A total of 288 HIV-infected persons underwent standardized neuropsychological testing. Participants were profiled based on neuropsychological and clinical assessments into 2 groups, neurocognitively normal (NN, n = 205) and HAND (n = 83). Risk-based decision-making was assessed via the Game of Dice Task (GDT). Sample characteristics were summarized by principal component analysis (PCA) prior to regression analyses predicting GDT performance. Results: The NN group performed within the normative range of the GDT, but the HAND group was impaired in all GDT measures. Across all participants, GDT performance was predicted by a combination of psychiatric comorbidities, alcohol abuse, education/premorbid IQ, and neuropsychological performance. Further analyses revealed marijuana use as an important additional predictor of impaired GDT performance. Within the GDT-impaired HAND group only, past or present immunosuppression emerged as the most robust predictor of GDT performance. Metabolic disorders and antiretroviral toxicity were also predictors of GDT performance in the HAND group. Conclusion: The majority of HIV-infected individuals were unimpaired in the GDT. Some influence of psychiatric and substance use comorbidities on GDT performance emerged in the entire cohort. However, GDT deficits were restricted to individuals with HAND, related to immunosuppression, metabolic disorders and antiretroviral toxicity in this group only.