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Background: In patients with chronic obstructive pulmonary disease (COPD) and acute respiratory failure, approximately 10% of them are considered to be at high risk for prolonged mechanical ventilation (PMV, > 21 days). PMV have been identified as independent predictors of unfavorable outcomes. Our previous study revealed that patients aged 70 years older and COPD severity were at a significantly higher risk for PMV. We aimed to analyze the impact of comorbidities and their associated risks in patients with COPD who require PMV., Methods: The data used in this study was collected from Kaohsiung Medical University Hospital Research Database. The COPD subjects were the patients first diagnosed COPD (index date) between January 1, 2012 and December 31, 2020. The exclusion criteria were the patients with age less than 40 years, PMV before the index date or incomplete records. COPD and non-COPD patients, matched controls were used by applying the propensity score matching method., Results: There are 3,744 eligible patients with COPD in the study group. The study group had a rate of 1.6% (60 cases) patients with PMV. The adjusted HR of PMV was 2.21 (95% CI 1.44-3.40; P < 0.001) in the COPD patients than in non-COPD patients. Increased risks of PMV were found significantly for patients with diabetes mellitus (aHR 4.66; P < 0.001), hypertension (aHR 3.20; P = 0.004), dyslipidemia (aHR 3.02; P = 0.015), congestive heart failure (aHR 6.44; P < 0.001), coronary artery disease (aHR 3.11; P = 0.014), stroke (aHR 6.37; P < 0.001), chronic kidney disease (aHR 5.81 P < 0.001) and Dementia (aHR 5.78; P < 0.001)., Conclusions: Age, gender, and comorbidities were identified as significantly higher risk factors for PMV occurrence in the COPD patients compared to the non-COPD patients. Beyond age, comorbidities also play a crucial role in PMV in COPD., (© 2024. The Author(s).)