The current study investigated the association between substance abuse/dependence, drug of choice, and the personality traits of negative emotionality, positive emotionality, and constraint (disinhibition) as measured by the Multidimensional Personality Questionnaire. The sample comprises 325 subjects from the Yale Family Study, a family study investigating the relation between substance-use disorders and anxiety disorders and their transmission in families. A total of 205 (63%) met criteria for lifetime substance abuse/dependence, with the remainder comprising the comparison group. The substance abusers were placed into one of four predominant drug of abuse/dependence categories (opioid, cocaine or stimulants, marijuana or sedatives, or alcohol) based upon best-estimate diagnoses and one of five self-reported drug of preference groups (polysubstance, opioid, cocaine or stimulants, marijuana or sedatives, and alcohol). First, findings demonstrate that individuals with substance abuse/dependence, compared to those without, scored lower on constraint even after adjusting for socio-demographic factors, comorbid psychiatric disorder, and current/remitted substance-use disorder. Individuals with substance abuse/dependence scored marginally higher on negative emotionality, but this difference was statistically significant only when comorbid psychopathology was not controlled. Second, findings show that individuals who differ with respect to drug of choice-whether defined in terms of the predominant drug of abuse/dependence or self-reported drug of preference-vary in terms of constraint. After controlling for socio-demographic indicators and comorbid psychopathology, scores on constraint generally decreased with the social deviance of the drug of choice, thereby underscoring a potentially important link between disinhibition and drug selection.