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Abstract Background/objective People living with HIV (PLWH) are prone to mental health problems and evidence indicates that HIV-related stigma can negatively impact mental health-related quality of life. This study explored potential mechanisms between HIV-related stigma and mental health-related quality of life, specifically whether anxiety or depression mediates, and whether social support moderates, the relationship. Method A total of 1197 Chinese PLWH participated in the study. The Berger HIV Stigma Scale, the Hospital Anxiety and Depression Scale (HADS), the 12-item Brief Health Survey (SF-12), and the Multidimensional Scale of Perceived Social Support (MSPSS) were employed. Results HIV-related stigma was negatively associated with mental health-related quality of life. Anxiety and depression partially mediated the relationship between HIV-related stigma and mental health-related quality of life; social support played a moderating role. Conclusions The mental health-related quality of life in PLWH was shown to be indirectly affected by HIV-related stigma through anxiety and depression in China. The negative impact of HIV-related stigma decreased with increased social support.