High prevalence of psychological distress, including greater depression, lower self-esteem, and suicidal ideation, has been documented across numerous samples of transgender women and has been attributed to high rates of discrimination and violence. According to the gender affirmation framework (Sevelius, 2013), access to sources of gender-affirmative support can offset such negative psychological effects of social oppression. However, critical questions remain unanswered in regards to how and which aspects of gender affirmation are related to psychological well-being. The aims of this study were to investigate the associations among 3 discrete areas of gender affirmation (psychological, medical, and social) and participants’ reports of psychological well-being. A community sample of 573 transgender women with a history of sex work completed a 1-time self-report survey that assessed demographic characteristics, gender affirmation, and mental health outcomes. In multivariate models, we found that social, psychological, and medical gender affirmation were significant predictors of lower depression and higher self-esteem whereas no domains of affirmation were significantly associated with suicidal ideation. Findings support the need for accessible and affordable transitioning resources for transgender women to promote better quality of life among an already vulnerable population. However, transgender individuals should not be portrayed simplistically as objects of vulnerability, and research identifying mechanisms to promote wellness and thriving is necessary for future intervention development. As the gender affirmation framework posits, the personal experience of feeling affirmed as a transgender person results from individuals’ subjective perceptions of need along multiple dimensions of gender affirmation. Thus, personalized assessment of gender affirmation may be a useful component of counseling and service provision for transgender women.