Apathy refers to decreased self-initiation and goal-directed behavior. Apathy is a relatively common neuropsychiatric symptom associated with HIV, yet the impact of apathy on health-related quality of life (QOL) has not been investigated. We examined the relationship between apathy, depression, and QOL among individuals infected with HIV. Apathy was quantified using the Marin Apathy scale and QOL was measured with the Medical Outcomes Study Short-Form 36 (SF-36). Results of the study revealed that both apathy and depression were more common among patients with HIV than healthy control subjects. Twenty-six percent of the patients with HIV reported clinically significant apathy while 80% of the patients reported clinically significant depression. Apathy did not relate to ratings of overall QOL, but it was modestly associated with ratings of mental health and role disruption secondary to mental health. By contrast, ratings of depression were strongly related to overall QOL and most indices of SF-36. Regression equations revealed that depression and apathy independently contributed to mental health and role disruption secondary to mental health. Importantly, ratings of depression accounted for the majority of variance for ratings of QOL. The findings indicate that while apathy is more common among individuals with HIV compared to healthy control subjects, the impact of apathy on QOL is less significant than depression. Clinicians should continue to focus on depression as an important neuropsychiatric symptom associated with HIV.