The atypical subtype of depression appears to be well validated and common, and it is unique among Axis I disorders in the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition (DSM-IV) in that it includes a personality trait, rejection sensitivity, as a criterion. Drug selection remains a challenge for the clinician who treats patients with this subtype of depression. Noradrenergic antidepressants have been thought to have prominent effects in improving-such symptoms as loss of motivation, drive, and energy, which are among the core symptoms of patients with atypical depression. Thus it can be speculated that noradrenergic antidepressants might be superior to serotonergic antidepressants in reducing symptoms of atypical depression. This is the first study to compare the efficacy of fluoxetine, a selective reuptake inhibitor of serotonin, and reboxetine, a selective reuptake inhibitor of norepinephrine, in the treatment of patients with atypical depression. A total of 43 patients with atypical depression according to DSM-IV were randomly assigned to receive fluoxetine or reboxetine over an 8-wk clinical trial. Patients with a Structured Clinical Interview for DSM-IV diagnosis of personality disorder accounted for 54% of those with atypical depression in this sample. Patients with personality disorders were typically young and were unable to maintain a marriage. Adverse effects such as dry mouth, sweating, headache, and urinary retention were more prominent in the reboxetine group than among those given fluoxetine. Although a greater number of patients treated with reboxetine dropped out of treatment, the pattern of response was very similar for both drugs, and both were effective in reducing symptoms of depression. The presence of a personality disorder in patients with atypical depression did not affect the response to either of the antidepressants. These findings might suggest that drugs with norepinephrine or a 5-hydroxytryptamine mechanism of action might act through a common pathway, resulting in a similar response in terms of core symptoms of depression. If tolerability, efficacy, and cost-effectiveness of antidepressants are considered, the best antidepressant is the one that can be used by the patient, whether or not a personality disorder accompanies atypical depression.