The purpose of this study was to determine whether any of the sociodemographic, biomedical, psychosocial, and medical-care factors independently predict health-related quality of life (HRQoL) among low-income women. Cross-sectional data were used to predict factors that determine HRQoL. A survey was conducted targeting a convenience sample of 200 midlife women. Blood samples were drawn from all participants, who also received a physical examination. Hierarchical multiple regression analysis was used to test the independent effects of each factor. The study found that sociodemographic and psychosocial factors were independently associated with HRQoL. Compared to married women, widowed or divorced women had significantly lower HRQoL, whereas those with higher levels of stress perception and those not performing regular exercise had significantly lower HRQoL (p < .01). The full model accounted for 44.7% of the variance in HRQoL. The HRQoL of low-income midlife women was associated with multiple factors, with stress perception exerting the major influence.