This study focused on the relationships among social support, self-esteem, and depression in transgender and cisgender individuals suffering from an incurable or curable sexually transmitted disease. Data were collected from 210 participants with an STI using a semi-structured interview along with culturally adapted standardized instruments. Results indicated no differences between transgender and cisgender groups in depression, although there were large differences in social support and self-esteem. Preliminary regression analysis identified only STI type and duration of STI as significant predictors of depression. However, when moderating roles for both social support and self-esteem were tested, each added to the explained variance and, equally importantly, revealed the effects of both gender status and social support on depression. These findings not only demonstrate how the compound stressors of gender minority status and STI type affect depressive symptoms, but also reveal the critical role that social support can play in mitigating depressive symptoms in those with gender minority status. Findings are interpreted within the context of South/Central Asian cultures that have pre- and post-colonial traditions regarding the social role of non-binary individuals.