© 2014 Taylor & Francis. Improving quality of life (QOL) for HIV-infected individuals is an important objective of HIV care, given the considerable physical and emotional burden associated with living with HIV. Although worse QOL has been associated with depression, no research has quantified the potential of improvement in depression to prospectively improve QOL among HIV-infected adults. We analyzed data from 115 HIV-infected adults with depression enrolled in a randomized controlled trial to evaluate the effectiveness of improved depression care on antiretroviral drug adherence. Improvement in depression, the exposure of interest, was defined as the relative change in depression at six months compared to baseline and categorized as full response (≥50% improvement), partial response (25-49% improvement), and no response (<25% improvement). Multivariable linear regression was used to investigate the relationship between improvement in depression and four continuous measures of QOL at six months: physical QOL, mental QOL, HIV symptoms, and fatigue intensity. In multivariable analyses, physical QOL was higher among partial responders (mean difference [MD] = 2.51, 95% CI: -1.51, 6.54) and full responders (MD = 3.68, 95% CI: -0.36, 7.72) compared to individuals who did not respond. Mental QOL was an average of 4.01 points higher (95% CI: -1.01, 9.03) among partial responders and 14.34 points higher (95% CI: 9.42, 19.25) among full responders. HIV symptoms were lower for partial responders (MD = -0.69; 95% CI: -1.69, 0.30) and full responders (MD = -1.51; 95% CI: -2.50, -0.53). Fatigue intensity was also lower for partial responders (MD = - 0.94; 95% CI: -1.94, 0.07) and full responders (MD = -3.00; 95% CI: -3.98, -2.02). Among HIV-infected adults with depression, improving access to high-quality depression treatment may also improve important QOL outcomes.