Countries worldwide have attempted to reduce the incidence of HIV and AIDS associated deaths with varying success, despite significant progress in antiretroviral treatment (ART) and condom use. A chief obstacles is that key populations affected face high levels of stigma, discrimination and exclusion, limiting the successful response to HIV. However, a gap exists in studies demonstrating the moderation effects of societal enablers on overall programme effectiveness and HIV outcomes using quantitative methods.Structural Equation Modeling was used for 138 countries covering a 12-year period to examine how the unfavorable societal enabling environment, including stigma and discrimination, unfavorable legal environment and lack of access to societal justice, gender inequality and other unfavorable development situations affect the effectiveness of HIV programmes and HIV outcomes, while controlling for potentially confounding variables. The results only showed statistical significance when all four societal enablers were modeled as a composite. The findings show the direct and indirect standardized effects of unfavorable societal enabling environments to AIDS-related mortality among PLHIV are statistically significant and positive (0.26 and 0.08, respectively). We hypothesize that this may be because an unfavorable societal enabling environment can negatively affect adherence to ART, quality of healthcare and health seeking behavior. Higher ranked societal environments increase the effect of ART coverage on AIDS related mortality by about 50% in absolute value, that is -0.61 as against -0.39 for lower ranked societal environments. However, mixed results were obtained on the impact of societal enablers on changes in HIV incidence through condom use. Results indicate that countries with better societal enabling environments had fewer estimated new HIV infections and fewer AIDS-related deaths. The failure to include societal enabling environments in HIV response undermines efforts to achieve the 2025 HIV targets, and the related 2030 Sustainable Development indicator to end AIDS, even if sufficient resources are mobilized.