The universal and disparaging nature of HIV stigma fuels discrimination, discourage HIV testing and treatment, and perpetuate cycles of marginalization in key populations, such as injecting drug users living with HIV/AIDS. Therefore, the objective of this research is to explore the correlation among HIV stigma, HIV-related communication, treatment adherence, and mental health in HIV positive injecting drug users in Pakistan. A cross-sectional survey research design was employed to recruit 200 consecutive participants purposively from the Mayo HIV Clinic, Lahore, Pakistan. HIV-positive injecting drugs users (IDU's) who were on follow-up treatment taking antiretroviral therapy (ART) were only recruited in this study. The study employed four established self-report measures: the HIV stigma scale, HIV-related communication scale, ART adherence measure, and an 18-item mental health inventory. Findings indicated that there is a significant negative association in HIV stigma and factors, such as HIV communication, treatment adherence, and mental health. Hierarchical regression analysis revealed that HIV-related communication and treatment adherence are significant positive predictors of mental well-being. Moreover, the parallel mediation model indicated that HIV communication and treatment adherence mediate in the association between HIV stigma and mental health. Addiction specialists and HIV clinicians must address issues, such as HIV related stigma and poor treatment adherence, as they are essential to enhance the overall well-being of HIV positive-IDUs. Furthermore, HIV clinicians must incorporate non-judgmental communication about HIV and simplified ART regimens to reduce the psychological toll of HIV stigma and treatment challenges.