Individuals with ADHD are at risk for substance use initiation in adolescence and escalation to problematic use in adulthood. Little is known about the impact of psychosocial ADHD treatment on substance use. Based on existing theory, both therapeutic (i.e., through reducing symptoms and impairments) and iatrogenic effects (i.e., through improved social functioning) of psychosocial treatment for ADHD on adolescent substance use initiation are plausible. A primarily ethnic/racial minority sample (~ 95% Latinx or Black) of rising ninth grade students with ADHD (n = 106) were randomly assigned to receive high intensity (i.e., Summer Treatment Program-Adolescent, parent training, and school consultation) or lower intensity (parent training, organization skills training, and school consultation) intervention the summer before entering high school. Participants were followed four-years post-baseline and substance use was documented. Analyses tested treatment effects on substance use initiation (alcohol and/or marijuana) and mediators of main effects. After controlling for covariates, participants assigned to HI (37.5%) were significantly more likely than LI (18.6%) to initiate substance use by end of high school, indicating an iatrogenic effect of HI treatment. No significant mediators were detected. Post-hoc exploration of moderators suggested that youth with elevated Posttraumatic Stress Disorder (PTSD) symptoms may have experienced a benefit of HI treatment on substance use whereas youth without elevated PTSD symptoms experienced iatrogenic effects. Large, well-powered, samples should examine moderated mediational models to better understand who is most risk for iatrogenic effects of ADHD psychosocial treatment and why. Clinicians delivering psychosocial treatment to adolescents with ADHD should monitor for potential iatrogenic effects.