The research addressed the question of whether relationships exist between personality dimensions, antisocial behavior, and alcohol or other substance misuse (AOSM) in adolescents and in their fathers and mothers, who often also have histories of AOSM. One hundred male adolescents (mean age 15.8 years) entering a residential treatment center for youths with AOSM, their mothers (n = 88, mean age 39.4 years), their fathers (n = 36, mean age 44.9 years), and community controls (n = 100 adolescents, mean age 16.5 years; n = 96 mothers, mean age 43.8 years; n = 87 fathers, mean age 45.9 years) were recruited. All participants completed a personality questionnaire and were interviewed on several measures, including structured interviews for psychopathology and substance misuse. The findings indicated that novelty seeking (NS), one of the personality dimensions, was significantly correlated with substance misuse in adolescent probands, adolescent controls, and proband fathers and mothers, but not in control fathers and mothers. Regression analyses that included conduct disorder (CD) or antisocial personality disorder (APD) symptoms indicated that both NS and CD or APD symptoms made significant contributions to the prediction of substance misuse in treatment group probands and in their fathers and mothers. The findings further suggest that NS and antisocial behaviors contribute independently to substance misuse in severely impaired adolescents and their fathers, but not in their mothers.