Abstract: Objective：To analyze factors related to weaning failure of prolonged mechanical ventilation (PMV) and corresponding intervention methods. Methods：The subjects included 40 patients who had undergone cardiac surgery and tracheotomy with PMV over 7 days. Cardiac function was assessed by echocardiography, pleural effusion and lung aeration were assessed by ultrasonography and computed tomography (CT), diaphragmatic function was assessed by diaphragm ultrasound. The rehabilitation exercise was performed. The readiness of weaning was evaluated regularly and the reasons for success or failure were analyzed. Results：Among the 40 patients, 8, 20, and 2 patients had cardiac dysfunction, respiratory dysfunction, and diaphragmatic dysfunction, respectively. Five patients had both cardiac and respiratory dysfunctions, 2 patients had both cardiac and diaphragmatic dysfunctions, and 3 patients had both respiratory and diaphragmatic dysfunctions. Among the 40 patients, 24 patients had weaning success and 16 had weaning failure. Cardiac dysfunction led to 80% of weaning failure, diaphragmatic dysfunction led to 28.5% of weaning failure, and respiratory dysfunction led to 20% of weaning failure. Univariate and multivariate analysis revealed that cardiac dysfunction was the risk factor that led to weaning failure (OR=3.431, 95%CI 1.083-10.867, P=0.036). PMV patients with initial respiratory insufficiency had lower failure rate (OR=0.039, 95%CI 0.001-0.751, P=0.003). PMV patients with diaphragmatic dysfunction did not affect the weaning outcome. Conclusions：Cardiac dysfunction may be the leading cause for weaning failure in cardiac surgical patients.