Objectives: To examine the six-year prognosis of patients with late-life depression and to identify prognostic factors of an unfavorable course. Design and Setting: The Netherlands Study of Depression in Older Persons (NESDO) is a multisite naturalistic prospective cohort study with six-year follow-up. Participants: Three hundred seventy-eight clinically depressed patients (according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision criteria) and 132 nondepressed comparisons were included at baseline between 2007 and 2010. Measurements: Depression was measured by the Inventory of Depressive Symptomatology at 6-month intervals and a diagnostic interview at 2- and 6-year follow-up. Multinomial regression and mixed model analyses were both used to identify depression-related clinical, health, and psychosocial prognostic factors of an unfavorable course. Results: Among depressed patients at baseline, 46.8% were lost to follow-up; 15.9% had an unfavorable course, i.e., chronic or recurrent; 24.6% had partial remission; and 12.7% had full remission at six-year follow-up. The relative risk of mortality in depressed patients was 2.5 (95% confidence interval 1.26–4.81) versus nondepressed comparisons. An unfavorable course of depression was associated with a younger age at depression onset; higher symptom severity of depression, pain, and neuroticism; and loneliness at baseline. Additionally, partial remission was associated with chronic diseases and loneliness at baseline when compared with full remission. Conclusions: The long-term prognosis of late-life depression is poor with regard to mortality and course of depression. Chronic diseases, loneliness, and pain may be used as putative targets for optimizing prevention and treatment strategies for relapse and chronicity.