The purpose of this study was to examine the causal relationships between age, antiretroviral treatment, social support, symptom experience, self-care strategies, and health-related quality of life (HRQOL). The subjects were 422 people living with HIV/AIDS. The data were collected via the Personal Resource Questionnaire 85 part 2, Symptom Experience Questionnaire, Self-care Strategies Questionnaire, and HRQOL Questionnaire. The results revealed that symptom experience had a significant negative direct effect on the HRQOL. Age, social support, antiretroviral treatment, and self-care strategies had a significant positive direct effect on the HRQOL. Moreover, social support and antiretroviral treatment had an indirect effect on the HRQOL via self-care strategies. The findings indicated that the health-care team should promote social support, both in the family and the community, including antiretroviral treatment, for enhanced HRQOL in people living with HIV/AIDS in the future.