Background: This study investigates the relationship between attention deficit hyperactivity disorder (ADHD) symptoms and cigarette smoking, alcohol use and illicit drug use. Method: The participants were 10,987 pupils in the final three years of their compulsory education in Iceland (ages 14-16 years). The participants completed questionnaires in class relating to anxiety, depression and antiestablishment attitudes, ADHD symptoms, smoking, alcohol consumption and illicit drug use. Results: Of the total sample, 5.4% met screening criteria for ADHD. Smoking, alcohol and illicit drug use were significantly related to ADHD symptoms. In addition, the number of different illicit drugs consumed was significantly higher among the ADHD symptomatic than the nonsymptomatic participants, including the illicit use of sedatives. The main distinguishing illicit drug substances were lysergic acid diethylamide (odds ratio or OR = 8.0), cocaine (OR = 7.5), mushrooms (OR = 7.1) and amphetamines (OR = 6.5). Logistic multiple regressions showed that after controlling for gender and school grade, ADHD symptoms predicted smoking, alcohol use and illicit drug use independent of anxiety, depression and antiestablishment attitudes. In addition, poly-substance use was linearly and incrementally related to ADHD symptoms with a large effect size. Conclusions: The findings underscore the vulnerability of young persons with ADHD symptoms to smoking, alcohol and illicit drug use, possibly as a means of self-medication, and emphasize a need for early identification and treatment to reduce the risk of escalation.