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Introduction Influenza vaccination (INV) and smoking cessation (SC) have individual positive effects on COPD, but their synergistic impact has yet to be extensively studied. This retrospective study aimed to assess the combined effect of SC and IV on the medical burden of COPD, including medical visits, hospitalization, medical expenses, and the occurrence of respiratory failure. Methods Patients with COPD who visited our medical center between January and October 2018 were included in the study. The patients were categorized into four groups: Group I (no SC or INV), Group II (INV only), Group III (SC only), and Group IV (both SC and INV). The outcomes analyzed were emergency utilization, hospital utilization, and occurrence of respiratory failure. Airflow limitation was stratified according to GOLD guidelines, and successful smoking cessation was defined as not smoking for at least one year. Results A total of 357 patients were included in the study. Group I (119 patients) neither smoking cessation nor influenza vaccination; Group II (66 patients) had only influenza vaccination; Group III (94 patients), had only smoking cessation, Group IV (78 patients), with both smoking cessation and influenza vaccination. Group IV had lower odds of emergency utilization (OR=0.13; 95% CI: 0.07–0.25), hospital utilization (OR=0.13; 95% CI: 0.05–0.30, p