We analyzed the relationship between depression and patient-assessed or clinician-rated work performance among chronically depressed patients followed for 12 weeks in a large clinical trial. The data were collected in a double-blind design comparing sertraline, a selective serotonin reuptake inhibitor, with imipramine, a tricyclic antidepressant, in 12 academic centers nationwide. Incorporating work-related questions from a portfolio of rating scales used to assess depression, we constructed several measures of work performance, assessed at baseline and at Week 12 of the clinical investigation, and examined how they changed with improvement in depressive symptoms. As depressive symptoms subsided following treatment, patients reported substantial improvement in our measures of work performance. Eighty-six percent of the cohort reported some improvement from base-line to Week 12. The extent of improvement in work performance correlates highly with improvement in the depressive symptoms measured on the Hamilton Rating Scale for Depression. Treatment of depression with antidepressant medications resulted in substantial improvement in subjective work performance among the patients studied.