IntroductionThere is strong global commitment to eliminate HIV-related stigma. Wide variation exists in frameworks and measures, and many strategies to prevent, reduce or mitigate stigma have been proposed but critical factors determining success or failure remain elusive.Methods and analysisBuilding on existing knowledge syntheses, we designed a systematic review to identify frameworks, measures and intervention evaluations aiming to address internalised stigma, stigma and discrimination in healthcare, and stigma and discrimination at the legal or policy level. The review addresses four key questions (KQ): KQ1: Which conceptual frameworks have been proposed to assess internal stigma, stigma and discrimination experienced in healthcare settings, and stigma and discrimination entrenched in national laws and policies? KQ2: Which measures of stigma have been proposed and what are their descriptive properties? KQ3: Which interventions have been evaluated that aimed to reduce these types of stigma and discrimination or mitigate their adverse effects and what are the effectiveness and unintended consequences? KQ4: What common ‘critical factors for success or failure’ can be identified across interventions that have been evaluated? We will search PubMed, PsycINFO, Web of Science, Universal Human Rights Index, HeinOnline, PAIS, HIV Legal Network, CDSR, Campbell Collaboration, PROSPERO and Open Science Framework. Critical appraisal will assess the source, processes and consensus finding for frameworks; COnsensus-based Standards for the selection of health Measurement Instruments criteria for measures; and risk of bias for interventions. Quality of evidence grading will apply . A gap analysis will provide targeted recommendations for future research. We will establish a compendium of frameworks, a comprehensive catalogue of available measures, and a synthesis of intervention characteristics to advance the science of HIV-related stigma.PROSPERO registration numberCRD42021249348.