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In June 2021, 40 years have passed since the first cases of HIV infection were detected. Nonetheless, people living with HIV (PLWH) still suffer from intense HIV-related distress and trauma, which is nowadays mostly linked to the still-existing stigmatization of PLWH. The aim of this systematic review and meta-analysis was to examine the association between HIV/AIDS stigma and psychological well-being among PLWH. We also explored whether this association varies as a function of sociodemographic and clinical characteristics as well as study publication year and stigma measurement. A structured literature search was performed on Web of Science, Scopus, PsyARTICLES, MedLine, ProQuest, and Google Scholar databases. The inclusion criteria were quantitative, peer-reviewed articles published in English between 1996 and 2020. After selection, 64 articles were accepted for further analysis (N = 25,294 participants). The random-effects pooled estimate revealed an overall negative and medium-strength association between stigma and well-being (r = −.31, 95% CI [−.35; −.26]). The participants' age modified this effect with a stronger association for older PLWH. Other sociodemographic and clinical variables as well as publication year and stigma measurement did not explain the variation in association between stigma and well-being across studies. The present meta-analysis and systematic review not only showed an expected negative relationship between stigma and well-being but also revealed a substantial heterogeneity between studies that suggests a strong role of context of a given study. This finding calls for more advanced theoretical and analytical models to identify protective and vulnerability factors to effectively address them in clinical practice and interventions. In this meta-analysis, the relationship between HIV/AIDS stigma and well-being of people living with HIV was investigated. [ABSTRACT FROM AUTHOR]