This study examined the relation of the Five-Factor Model (FFM) of personality to symptoms of alcohol and marijuana abuse before and after controlling for symptoms of antisocial personality disorder (APD) and internalizing psychopathology. The 481 participants completed a well-validated measure of the FFM and a structured diagnostic interview at age 21 years. Hierarchical regression analyses indicated that unique constellations of personality characteristics were associated with symptoms of alcohol abuse, marijuana abuse, APD, and internalizing disorders. For example, symptoms of alcohol abuse were associated with high Extraversion and low Conscientiousness, whereas symptoms of marijuana abuse were characterized by low Extraversion and high Openness to Experience. Findings have implications for models of the etiology and treatment of substance use and abuse.