Understanding factors influencing mental health and substance use in transgender and gender diverse people is critical to reducing disparities in this population. We sought to investigate whether a history of sex work was associated with increased prevalence of poor mental health, substance use, and a negative experience within drug and alcohol treatment facilities. We conducted a secondary analysis of the data of 25,204 transgender respondents of the 2015 United States Transgender Survey. We estimated multiple logistic regressions to assess the association between a history of sex work and adverse mental health and substance use outcomes. We then estimated mean prevalence of adverse outcomes by type of sex work. Finally, we performed chi-square analysis to explore differences in mistreatment at drug and alcohol treatment facilities. Respondents with a history of sex work were significantly more likely to have poorer psychological health, suicidality, and substance use after adjusting for covariates. Among those who visited drug and alcohol treatment facilities, those with a history of sex work were significantly more likely to report adverse experiences (26.34% vs. 11.63%). Our findings highlight the increased risk of adverse outcomes in transgender sex workers and emphasize the need for interventions targeting this subgroup of transgender people.