This cross-sectional study examined physical, psychological, and social factors associated with quality of life (QOL) among a sample of 399 rural women with HIV disease living in the Southeastern United States. Of the socio-demographic variables, age (p = .003), race (p < .0001), and time of HIV diagnosis (p = .03) were significantly associated with QOL. In bi-variate analysis, HIV symptoms (frequency and extent symptoms were bothersome), perceived stigma, internalized stigma, and depression were significantly and negatively associated with QOL whereas social support, problem-focused coping, perceived situational control, and healthy lifestyles were significantly and positively associated with QOL (all p < .0001). In adjusted analysis, HIV symptom frequency, depression, problem-focused coping, perceived situational control, perceived stigma, healthy lifestyles, and race remained significant predictors of QOL and explained 55% of the variance in QOL among the study participants (model F (7, 390) = 66.7; p < .0001). The study findings identify potential points of interventions to improve QOL among rural women with HIV disease.