In this study HIV health-related quality of life (HIV-HRQOL) is examined among 179 behaviorally infected adolescent and young adult women. Modifiable psychosocial variables including depression, stigma, social support, and illness acceptance, and the biological end-points of CD4 cell count and viral load were explored in relation to HIV-HRQOL. The three factors of the HIV-HRQOL measure include current life satisfaction, illness related anxiety and illness burden. Bivariate linear regression analysis demonstrated statistically significant associations for all psychosocial variables and HIV HRQOL factors (p < .01), but not for biological end-points. In multivariate linear regression analysis significant associations remained between: depression (p = .006), illness acceptance (p < .001), social support (p = .001), and current life satisfaction, and depression (p = .012), illness acceptance (p = .015), and illness burden. A trend in association was noted for HIV stigma, with current life satisfaction and illness related anxiety but did not reach statistical significance (p = .097 and p = .109 respectively). Interventions that effectively decrease stigma and depression and increase social support and illness acceptance will likely improve the well-being and quality of life of HIV-infected adolescent women.