We assessed whether multiple psychosocial factors are additive in their relationship to sexual risk behavior and self-reported HIV status (i.e., can be characterized as a syndemic) among young transgender women and the relationship of indicators of social marginalization to psychosocial factors. Participants (n = 151) were aged 15 to 24 years and lived in Chicago or Los Angeles. We collected data on psychosocial factors (low self-esteem, polysubstance use, victimization related to transgender identity, and intimate partner violence) and social marginalization indicators (history of commercial sex work, homelessness, and incarceration) through an interviewer-administered survey. Syndemic factors were positively and additively related to sexual risk behavior and self-reported HIV infection. In addition, our syndemic index was significantly related to 2 indicators of social marginalization: a history of sex work and previous incarceration. These findings provide evidence for a syndemic of co-occurring psychosocial and health problems in young transgender women, taking place in a context of social marginalization.