BACKGROUND: The clinical and etiological significance of the early-late onset distinction in chronic major depressive disorder was explored. METHOD: Subjects were 289 outpatients with DSM-III-R chronic major depression drawn from a multi-site study comparing the efficacy of sertraline and imipramine in the acute and long-term treatment of chronic depression. Patients received comprehensive evaluations using semi-structured interviews and rating scales. RESULTS: Early-onset chronic major depression was associated with a longer index major depressive episode and higher rates of recurrent major depressive episodes, comorbid personality disorders, lifetime substance use disorders, depressive personality traits, and a history of psychiatric hospitalization. In addition, more early-onset patients tended to have a family history of mood disorders. The early-late onset distinction was not associated with differences in symptom severity, functional impairment, or treatment response. LIMITATIONS: Family members were not interviewed directly; there were a large number of statistical comparisons; and interrater reliability of the assessments was not evaluated. CONCLUSIONS: Early-onset chronic major depression has a more malignant course and is associated with greater comorbidity than late-onset chronic major depression.