The comorbidity of DSM-III-R axis I and axis II disorders presents conceptual and nosological challenges to psychiatry. In a consecutive series of 164 psychiatric outpatients and 36 healthy controls in Milan, Italy, psychopathology was measured by structured interviews for DSM-III-R disorders and temperament was measured by the Tridimensional Personality Questionnaire (TPQ). Low reward dependence (RD) distinguished cluster A personality disorders and no axis I disorders. High novelty seeking (NS) characterized cluster B personality disorders and patients with eating disorders, alcohol abuse, or substance abuse. High harm avoidance (HA) characterized all cluster C personality disorders and patients with mood or anxiety disorders. The temperament dimensions were nearly independent of one another, but patients often had multiple DSM-III-R diagnoses. The joint relations of these disorders to multiple temperament dimensions accounted for their characteristic patterns of comorbidity. These findings support the hypothesis that interactions among temperament dimensions during development influence comorbidity between axis I and axis II disorders.