Neuropsychological impairment and depression are common among individual with HIV-infection, resulting in significantly altered everyday functioning. The objective of this study was to examine the impact of these two important neurobehavioural complications on health-related quality of life in adults with HIV-infection. Participants (n = 155) received a 3-hours comprehensive neuropsychological examination, the Beck Depression Inventory, and the Medical Outcomes Study HIV Quality of Life instrument. Four groups were formed based on the presence or absence of depression and neuropsychological impairment. Results suggest that neuropsychological impairment and depression can differentially affect dimensions of health-related quality of Life. Specifically, depression has a significant impact on mental health dimensions of health-related quality of life. Some evidence exists for an impact of neuropsychological impairment, or a combined impact of depression and neuropsychological impairment, on the Physical Health dimensions of health-related quality of life. These results confirm the importance of depression as a determinant of health-related quality of life in HIV/AIDS and provide a potential avenue for improving health-related quality of life in adults with HIV-infection.