Background: Post-traumatic stress disorder (PTSD) and substance use disorders (SUDs) often co-occur in adolescent patients. Previous research has shown that these patients differ from SUD patients without PTSD in terms of their substance use patterns. In this study, we aimed to test whether substance use in this population is related to an attempt to self-medicate PTSD-related symptoms. Methods: German adolescent patients (aged 13–18 years) at an outpatient clinic for SUD treatment, n = 111 (43% female), completed a self-designed questionnaire on use motives, a measure of PTSD-related experiences, and underwent a standardized psychiatric interview including structured substance use questions. Participants were subsequently classified as ‘no traumatic experiences (‘noTEs’ but SUD), ‘traumatic experiences but no current PTSD diagnosis’ (‘TEs’ with SUD), and ‘PTSD’ with SUD. After establishing a self-designed motive measurement through exploratory and confirmatory factor analyses, we calculated non-parametric group differences and a mediation analysis in a linear regression framework. Results: The past-year frequency of MDMA use was highest in the PTSD group and lowest in the noTE group (H (2) = 7.2, p =.027, η2 =.058), but no differences were found for frequencies of tobacco, alcohol, cannabis, or stimulant use (all H ≤ 4.9, p ≥.085, η2 ≤.033). While controlling for sex, the three groups showed a similar pattern (highest in the PTSD group and lowest in the noTE group) for coping scores (F (103) = 5.77, p =.004, η2 =.101). Finally, mediation analyses revealed an indirect effect of coping score (b = 0.61, 95% CI [0.29, 1.58], p =.145) on the association between group membership and MDMA use frequency. Conclusions: In adolescent SUD patients, we found an association of current PTSD and lifetime traumatic experiences with higher MDMA use that could be partially explained by substance use being motivated by an attempt to cope with mental health symptoms. This indicates a coping process involved specifically in MDMA use compared to the use of other psychoactive substances, possibly due to unique psychoactive effects of MDMA.