Background: Fifteen to 25-year-olds are the age group most likely to misuse prescription drugs. Few studies have tested theory-driven models of adolescent risk for prescription drug misuse. Moreover, rarely are distinct pathways to different forms of prescription drug misuse considered.Methods: We tested mediational paths from personality to mental health symptoms to prescription drug misuse, informed by etiological models of addiction. We specified pathways from particular personality traits to unique forms of prescription drug misuse via specific mental health symptoms. We used semi-longitudinal data collected across two waves of the Co-Venture Trial. Our sample included students from 31 Canadian high schools tested in Grade 9 (n = 3,024) and again in Grade 10 (n = 2,869; 95% retention). Personality (hopelessness, anxiety sensitivity, impulsivity, sensation seeking) was assessed in Grade 9. Mental health symptoms (depression, anxiety, ADHD, conduct disorder) and prescription drug misuse (opioids, sedatives/tranquilizers, stimulants) were assessed at both time points.Results: Consistent with the negative affect regulation model, hopelessness was specifically associated with opioid misuse via depressive symptoms, and anxiety sensitivity was specifically associated with sedative/tranquilizer misuse via anxiety symptoms. Consistent with positive affect regulation, sensation seeking was directly associated with stimulant misuse. Consistent with the psychological dysregulation model, impulsivity was associated with stimulant misuse via ADHD symptoms. And consistent with the deviance proneness model, impulsivity was also associated with unconstrained (i.e., all three forms of) prescription drug misuse via conduct disorder symptoms.Conclusions: Screening for adolescents high in hopelessness, anxiety sensitivity, sensation seeking, or impulsivity and providing them with personality-matched cognitive-behavioral interventions may be helpful in preventing or mitigating prescription drug misuse. Our results point to the specific mental health symptoms that are important to target in each of these personality-matched interventions.