No known studies have investigated co-occurrence of psychopathology problems in adolescents with biologic and/or environmental susceptibility, including prenatal drug exposure. This study identified comorbidity patterns of psychopathology problems by utilizing data from urban, primarily African American, youth, majority of whom were at heightened risk for exposure to drugs in utero. The roles of Research Domain Criteria (RDoC)-informed behavioral constructs of the Negative Valence (irritability) and Social Process Systems (social disinhibition) as antecedents of the comorbidity patterns were further examined. Lastly, the predictive validity of the identified patterns was evaluated in relation to emerging adulthood outcomes. Participants were 358 urban adolescents, primarily African Americans, drawn from a 21-year prospective birth-cohort study of the effects of prenatal drug exposure. Psychopathology problems were assessed at age 15. Irritability and social disinhibition were self-reported at age 12. Emerging adulthood outcomes were measured at age 21. Latent class modeling indicated four patterns: Normative (57%), substance-use (SU; 24%), mental-health-problems-without-substance-use (MH; 11%), and substance-use-and-other-mental-health-problems (SUMH; 7%). Higher irritability increased the odds of developing the MH pattern, whereas higher social disinhibition increased the odds of developing the SU pattern. The odds of manifesting the SUMH pattern were higher for children with higher irritability. For children with higher social disinhibition, the odds of manifesting the SUMH pattern were higher at a trend level. Adolescent comorbidity patterns were differentially associated with problematic tobacco and marijuana use and clinically relevant mental health problems in emerging adulthood, and completion of high school education. Peri-pubertal identification of individual differences in irritability and social disinhibition may mitigate the emergence of adolescent psychopathology, which could influence emerging adulthood adjustment in this at-risk population.