To explore the use of normal personality measures in clinical populations, we investigated the usefulness of the Five-Factor personality domains measured by the NEO Personality Inventory (NEO-PI) in identifying subtypes among a cohort of 3,256 substance abusers. Three groups were reliably identified across clustering methods and the groups differed in reported coping style, psychopathological symptoms, and pattern of substance choice. The largest differences between group members' personality dimensions were found for measures of neuroticism, agreeableness, and conscientiousness. Members of groups characterized by elevated levels of neuroticism demonstrated low levels of conscientiousness and agreeableness. The more extreme the group members' levels on these personality dimensions, the higher their reported levels of depressive symptoms, aggressive/hostile cognitions, impulsiveness, maladaptive coping styles, and likelihood of abusing more than one substance. Results support the use of measures of normal domains of personality in identifying meaningful subtypes of substance abusers.