A strong global commitment exists to eliminate HIV-related stigma and discrimination, and multiple strategies to reduce or eliminate stigma and discrimination have been tried. Using a PICOTS framework and applying the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) criteria, we undertook a systematic review to determine the success of interventions aiming to address internalized stigma, stigma and discrimination in healthcare, and at the legal or policy level, and to identify their critical success factors. Random effects meta-analyses summarized results wherever possible. We carried out a component analysis to identify and characterize successful interventions. Internalized stigma interventions were diverse: across all studies, we found a reduction of stigma but it was not statistically significant [standardized mean difference (SMD) 0.56; confidence interval (CI) 0.31-1.02; 17 studies). For interventions to address stigma and discrimination in healthcare settings, effect estimates varied considerably but most studies showed positive effects (SMD 0.71; CI 0.60-0.84, 8 studies). Boosted regression analyses found that a combined approach comprising education, counseling, community participation, support person, and access to a HIV specialist often yielded success. Studies of efforts to address stigma and discrimination through law and policy documented, mostly qualitatively, the effect of court cases and directives. Across a range of settings and populations, promising interventions have been identified that, through diverse pathways, have positively impacted the types of stigma and discrimination studied. This evidence base must be built upon and brought to scale to help reach global HIV-related targets and, most importantly, improve the health and quality of life of people with HIV.