Recent investigations suggest that serotonergic mechanisms modulate dimensions of personality, in particular decreases in Anger-Hostility and increases in Affiliation. None of these studies, however, demonstrated a specific serotonergic effect on personality, as other neurotransmitter systems have not been assessed for their impact on these personality dimensions. In this study, 76 depressed outpatients were treated with either the noradrenergic antidepressant desipramine (n = 38) or a selective serotonin re-uptake inhibitor (paroxetine or sertraline) (n = 38) over a period of 8-14 weeks. Personality scores were measured pre- and post-treatment using the revised NEO Personality Inventory, which measures five basic dimensions of personality, with subscales assessing Anger-Hostility and Affiliation (Gregariousness). There was a significant decrease in Neuroticism and Anger-Hostility, and a significant increase in Extraversion and Gregariousness following antidepressant treatment. Although changes in neuroticism and extraversion were significantly correlated with change in depression severity, Anger-Hostility and Gregariousness personality scores were not. Therefore, changes in these personality traits were not attributable to a non-specific effect of medication on changes in depression severity. There were no significant differences in personality change scores between the antidepressant treatment groups. Thus, while antidepressants may have a direct effect on neurochemical pathways relevant to personality, independent of changes in depression severity, these effects cannot be directly or specifically attributed to a serotonergic mechanism.