Objectives This study aimed to explore significant childhood ADHD symptomatology, psychiatric comorbidity, rates of Substance Use Disorders (SUD), as well as their association with high-risk health behaviors and adverse health outcomes in prison. Method A randomly selected representative sample of inmates in the Puerto Rico correctional system (n = 1,179) were assessed with the Spanish language Wender Utah Rating Scale (WURS), the CIDI modules for lifetime/current MDD, GAD and SUD, the Davidson Trauma Scale (DTS, PTSD), and self-reports of in-site high risk behaviors. Results Wald χ2 tests revealed significant associations of ADHD with MDD, GAD and PTSD, as well as increased risk for overdosing and IV drug use in prison. A Logistic Regression model adjusted for mood and anxiety comorbidity predicted lifetime SUD diagnosis (OR 2.38; CI 1.15–4.94). Discussion Our results provide evidence on the extent of the association of drug dependence and ADHD symptoms, and their over-representation among prison inmates.