Objective: To examine the influence of specific chronic somatic diseases and overall somatic diseases burden on the course of depression in older persons. Methods: This was a prospective cohort study with a 2-year follow-up. Participants were depressed persons (n = 285) from the Netherlands Study of Depression in Older Persons. The presence of chronic somatic diseases was based on self-report. Diagnosis of depression was assessed with the Composite International Diagnostic Interview, and severity of depression was measured with the Inventory of Depressive Symptomatology Self-report. Results: Cardiovascular diseases (odds ratio [OR] = 1.67, 95% confidence interval [CI] = 1.02–2.72, p = 0.041), musculoskeletal diseases (OR = 1.71, 95% CI = 1.04–2.80, p = 0.034), and the number of chronic somatic diseases (OR = 1.37, 95% CI = 1.16–1.63, p < 0.001) were associated with having a depressive disorder at 2-year follow-up. Furthermore, chronic non-specific lung diseases, cardiovascular diseases, musculoskeletal diseases, cancer, or cumulative somatic disease burden were associated with a chronic course of depression. Conclusions: Somatic disease burden is associated with a poor course of late-life depression. The course of late-life depression is particularly unfavorable in the presence of chronic non-specific lung diseases, cardiovascular diseases, musculoskeletal diseases, and cancer.