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Background: HIV/AIDS has transformed into a chronic controllable but not yet curable infectious disease as other chronic diseases to some extent. The additional of so called fourth 90% that included the improved health-related quality of life (HRQoL) for people living with HIV (PLWHIV) required solutions beyond antiretroviral therapy and viral load suppression. This study will explore the role of personality, social economic and prevention strategy effection on HRQoL among people living with HIV/AIDS. Methods: A cross-sectional study was conducted among PLWHIV aged more than 16 years old in the 10 municipalities in Yunnan Province, China from October 2019 to May 2020, enrolling total 1997 participants. Individual-level HRQoL data were measured by 12-item Short Form Health Survey (SF-12) and EuroQol Five Dimensions Questionnaire (EQ-5D-5L). We assembled municipal-level data about social economic from Yunnan Statistical Yearbook in 2020 and strategy practice information from the self-evaluation system. We used the principal component analysis to build the social economic and strategy effect on each area respectively and one-way ANOVA was used to perform univariate analysis to identify the predictors with significant differences. Finally we used multi-level model (MLM) to explore the personality, social economic and strategy effects in health-related quality of life among PLWHIV. Results: The global score for quality of life measured using EQ-5D-5L had an estimated mean score (standard deviation, SD) of 0.901 ± 0.146. The HRQoL score measured using PCS-12 had an estimated mean score (SD) of 46.62 ± 8.55. The mean MCS-12 score (SD) was estimated to be 47.80 ± 9.71. The area-level predictors explained a proportion of 13.6–17.2% for the between-area variation of the HRQoL scores, regardless of the total HRQoL, physical component and mental component. The impacts of stigma (P < 0.01), social support (P < 0.001), anxiety (P < 0.001), depression (P < 0.05) and social economic status (P < 0.05) on HRQoL at the individual-level were significantly different. The plots visualized the impact of individual-level factors on a respondent's HRQoL was modified by the area-level characteristics. Conclusions: The study identified the possible strategy determinant of individual HRQoL of PLWHIV and also the area effect on HRQoL. Stigma, social support, anxiety, depression and social economic status were the individual-level determinants on HRQoL. These could be a valuable resource for evaluating the overall health of the areas and help improve local decision making. [ABSTRACT FROM AUTHOR]