Objective: The naturalistic course of major depressive disorder (MDD) and risk indicators for recurrence and chronicity are best studied using a population sample without clear selection bias. However, such studies are scarce. This limits clinical decision-making concerning monitoring and maintenance treatment. Method: Data were used from the Netherlands Mental Health Survey and Incidence Study-2, a psychiatric epidemiological cohort study among a representative adult population. Two groups at baseline were selected to study recurrence and chronicity of MDD at follow-up. Diagnoses were assessed with the Composite International Diagnostic Interview 3.0. Results: Among remitted MDD cases (n = 746), the cumulative recurrence rate was 4.3% at 5 years, 13.4% at 10 years and 27.1% at 20 years. Time to recurrence was predicted by vulnerability characteristics (childhood abuse, negative life events, parental psychopathology), physical health, functioning, clinical characteristics of depression (previous episodes, severity, medication use), psychiatric comorbidity and mental health use. Among current MDD cases (n = 242), 12% developed a chronic depressive episode over 6 years. Chronic course was predicted by similar risk indicators as recurrence, except for vulnerability characteristics and physical health. Conclusion: These risk indicators may help to identify patients requiring monitoring and who could benefit from preventive interventions or maintenance treatment.