The purpose of this secondary analysis was to test Ferrans et al.'s (J Nurs Scholarsh 37(4):336-342, 2005) revised model of health-related quality of life (HRQoL) (2005) modified from the Wilson and Cleary (J Am Med Assoc 273(1):59-65, 1995) model on women living with HIV. The primary aim was to test this model, examining the relations among the five central components (biological function, symptoms, functional status, general health perceptions, and HRQoL). The secondary aim was to explore the individual (age, children, race, marital status, education) and environmental (HIV-related stigma, social support) characteristics that may impact the main components of the model. This study employed a cross-sectional correlational design using baseline data from 178 women living with HIV/AIDS who participated in one of the two independent randomized controlled trials designed to enhance HIV medication adherence. Path analysis using structural equation modeling was used to examine the hypothesized multivariate relations proposed in the revised Wilson and Cleary (J Am Med Assoc 273(1):59-65, 1995) model of HRQoL. While the revised model did not fit, exploratory post hoc modified models with a path from depressive symptoms to overall general health had an adequate model fit. Women with lower depressive symptoms (r = -.457, p < .01), lower HIV-related stigma (r = -.462, p < .01), higher social support (r = .413, p < .01), higher physical functioning (r = .350, p < .01), and higher general health perceptions (r = .537, p < .01) had higher overall HRQoL. The results of this study have the potential to assist healthcare professionals in improving HRQoL for women living with HIV/AIDS.