OBJECTIVES: Although it is known that depression and anxiety can affect the prognosis of asthma or COPD, few studies have reported their effects on asthma-COPD overlap (ACO) in which a patient presents symptoms of both asthma and COPD. We assessed the associations of depression and anxiety with exacerbations in ACO. METHODS: Using the Korean National Sample Cohort database, ACO cohort included patients ≥ 40 years who fulfilled the following criteria between 2003 and 2011: (1) diagnosed with COPD (ICD-10-CM, J42-J44) more than twice and prescribed COPD medications, (2) diagnosed with asthma (J45-J46) more than twice and prescribed asthma medications. Index date was defined as the first date that both criteria were met. Comorbid depression and anxiety were identified as depression (F32-F33) and anxiety (F40-F42) diagnoses within 1 year before the index date. Exacerbation was defined as being prescribed a high-dose oral corticosteroid (CS) for ≥ 3 days or one systemic CS injection for 2 years of follow-up and categorized based on the types of medical utilization; outpatient visits, hospitalization, and emergency department (ED) visit. Logistic regression was used to estimate the associations of depression or anxiety with exacerbations, adjusting for patient demographics and clinical characteristics of 1-year pre-index period. RESULTS: The study included 15,648 ACO patients (43% ≥ 65 years; 50% female). After adjustment, ACO patients with depression showed a doubled risk of ED visit (95% CI 1.30-3.08) and 1.20-fold increased risk of hospitalization (95% CI 1.01-1.43). In contrast, ACO patients with anxiety showed 1.31-fold increased risk of outpatient visit (95% CI 1.16-1.48) and 1.23-fold increased risk of hospitalization (95% CI 1.08-1.40). CONCLUSIONS: This study provides real-world evidence on the associations of depression and anxiety with exacerbations in ACO patients. Given the struggle of clinicians to prevent exacerbations, more attentions are needed to comorbid depression and anxiety in ACO patients.