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Background: People living with human immune deficiency virus (PLHIV) grapple with distinct challenges, including HIV stigma which affects their antiretroviral therapy (ART) adherence self-efficacy. This study investigates the interaction of HIV stigma and perceived social support on ART adherence self-efficacy among adult PLHIV in South Africa., Methods: This study utilized a cross-sectional design that involved 201 participants selected using time location sampling at a tertiary health facility in Durban., Results: HIV stigma was significantly and negatively associated with self-efficacy (β = -7.860, t  = -4.654, p  = .001), with variations across different stigma levels (β = -5.844, t  = -4.003, p  = .001). Social support was significantly and positively associated with self-efficacy at lower HIV stigma levels (β = 7.440, t  = 3.887, p  = .001), in contrast to higher levels (β = -2.825, t  = 1.400, p  = .163)., Conclusion: Social support significantly influences ART adherence self-efficacy, particularly at lower levels of HIV stigma, but the effect of support weakens as stigma intensifies., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.