Adolescent substance use is a major public health concern since it enhances adolescent morbidity and mortality, affecting adulthood health and well-being. Although current evidence shows a high risk for substance use among transgender populations, to date, few studies evaluate substance use among transgender youth.Brazilian transgender youth (ages between 16 and 25 years old) answered an online questionnaire measuring demographics, substance use and modifiable factors associated with drug use to deal with general stress, gender-related stress, and recreational use.Cannabis was the most frequent substance used among transgender youth (20.88%; CI 95% 23.71-36.19), whereas 11.45% (CI 95% 11.38-21.47) of volunteers disclosed use of pain medication, such as codeine, and 5.05% (CI 95% 3.71-10.78) revealed use of sedatives and tranquilizers in the last 30 days. ADH medication (not prescribed), as well as cocaine and other drugs (such as antihistamines and Hookah), was also reported by 2.36% (CI 95% 0.92-5.84), 2.69% (CI 95% 1.24-6.49) and 4.04% (CI 95% 2.61-8.98) of transgender youth.A logistic regression model showed that discrimination and home instability were the primary determinants of vulnerable to substance use among youth. Therefore, the harm reduction strategies must affect the social and physical aspects of transgender youth lives.