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Racial minority men who have sex with men (MSM) experience greater levels of discrimination and higher rates of HIV infection. However, little is known about the associations between racial and heterosexist discrimination and HIV risk behavior. Further, little is known about the mechanisms of the association between racial and heterosexist discrimination and HIV risk behavior. There is some evidence to suggest that depression may be a mechanism that mediates the relationship between racial and heterosexist discrimination and HIV risk behavior. Thus, one purpose of this study was to investigate the extent to which discrimination based on both race and sexual orientation, alone and in combination, are associated with HIV risk behavior. A secondary purpose of this study was to examine whether the relationship between discrimination and HIV risk behavior is mediated by depressive symptoms. Lastly this study sought to examine whether the relationships between discrimination, depressive symptoms, and HIV risk behavior were mediated by social support, LGBT and Native identity, and LGBT and Native community participation. This study analyzed data from the HONOR project, the first national study of two-spirit individuals, which included 221 American Indian and Alaska Native MSM. Logistic regression analyses were conducted to determine the extent to which experiences of racial and heterosexist discrimination were associated with HIV risk behavior. Results indicate that heterosexist discrimination was associated with HIV risk behaviors, whereas racial discrimination was not. Conversely, results indicate that racial discrimination was associated with depressive symptoms, whereas heterosexist discrimination was not. This study found no association between depressive symptoms and HIV risk behavior, even when accounting for alcohol and substance use. Results indicate that depressive symptoms are not a mechanism that explains the association between discrimination and HIV risk and perhaps the better mechanism to examine in future studies is substance use. Finally, LGBT community participation was shown to have protective effects against HIV risk behaviors. These findings have the potential to guide development of mental health and HIV prevention interventions for Native MSM, with special attention to LGBT community participation and social support. Future research should examine attributes such as types, sources, and frequency of heterosexist discrimination and LGBT community participation.