What accounts for differences in HIV stigma across different high prevalence settings? This study was designed to examine HIV stigma and discrimination in five high prevalence settings. Qualitative data were collected as part of the U.S. National Institute of Mental Health (NIMH) Project Accept, a multi-site community randomized trial of community-based HIV voluntary counseling and testing. In-depth interviews were conducted with 655 participants in five sites, four in Sub-Saharan Africa and one in Southeast Asia. Interviews were conducted in the local languages by trained research staff. Data were audiotaped, transcribed, translated, coded and computerized for thematic data analysis. Participants described the stigmatizing attitudes and behaviors perpetuated against people living with HIV/AIDS (PLWHA). The factors that contribute to HIV stigma and discrimination include fear of transmission, fear of suffering and death, and the burden of caring for PLWHA. The family, access to antiretrovirals and other resources, and self-protective behaviors of PLWHA protected against HIV stigma and discrimination. Variation in the availability of health and socioeconomic resources designed to mitigate the impact of HIV/AIDS helps explain differences in HIV stigma and discrimination across the settings. Increasing access to treatment and care resources may function to lower HIV stigma, however, providing services is not enough. We need effective strategies to reduce HIV stigma as treatment and care resources are scaled up in the settings that are most heavily impacted by the HIV epidemic.