Reducing HIV/AIDS-related stigma is critical in the fight against HIV/AIDS. Although national campaigns and prevention programs have been implemented across South Africa to address this critical concern, assessing the impact of these initiatives is difficult as it requires that measurement of HIV/AIDS-related stigma is uniform and comparable nationwide. The appropriateness of existing stigma measures for this task is unclear as measurement of HIV/AIDS-related stigma may be qualitatively different across South Africa’s diverse population. The current study assesses a theoretically and culturally informed multidimensional, HIV/AIDS-related stigma scale for measurement invariance across a sample drawn from two culturally distinct South African provinces: Limpopo (n = 597) and Western Cape (n = 598). Results suggest measurement invariance across groups for the HIV/AIDS stigma scale, supporting the scale’s integrity and appropriateness for use across diverse populations.