The primary aim of this descriptive correlational study was to determine which domains of health related quality of life (HRQOL) after controlling for demographic correlates predict depressive symptoms among N = 70 seropositive African American men and women on Active Antiretroviral Therapy (ART). A demographic questionnaire, the Center for Epidemiological Studies Depression Scale (CESD-D), and the SF-36 Health Related Quality of Life (HRQOL) scale were administered. The regression analyses resulted in three models. The first model indicated that emotional well-being explained 38% of the variance in depressive symptoms (P = 0.000) and in model two, emotional well-being and role limitations on emotional health explained 50% of the variance (P = 0.000) and in the final and best fitting model emotional well-being, role limitations on emotional health and pain explained 53% of the variance in depressive symptoms (P = 0.000) respectively. The findings underscore the need to explore the impact of HRQOL on mental health, and to also screen and treat seropositive African American men and women on (ART) for depressive symptoms. (C) 2016 Published by Elsevier Inc.