Introduction: We aimed to elucidate the risk factors of ventilation dependency following cardiac surgery for infective endocarditis. Methods: We retrospectively investigated patients with infective endocarditis undergoing cardiac surgery. Mechanical ventilation > 72 hours was defined as ventilation dependency following cardiac surgery. Results: 896 patients with infective endocarditis undergoing cardiac surgery were divided into group of mechanical ventilation ≤ 72h (n = 702) and > 72h (n = 192). Multivariate analyses identified age, time between symptoms and surgery, vegetation length, aortic cross-clamp time, cardiopulmonary bypass time, ICU retention time, serum creatinine before and 24h after surgery, preoperative and postoperative LVEDD, preoperative aortic insufficiency and packed red cells to be associated with ventilation dependency following cardiac surgery; ventilation dependency is significantly related to prolonged ICU stay (>3d), 1- and 5-year mortality following cardiac surgery. All-time mortality (45.3% versus 5.6%, P<0.001) in group of mechanical ventilation >72h was significantly higher than that in group of mechanical ventilation ≤ 72h. A significant positive correlation exists between preoperative aortic insufficiency and ventilation dependency following cardiac surgery. A value of preoperative aortic insufficiency > 5.25 cm2 was 100% sensitive and 64.6% specific for the diagnosis of ventilation dependency following cardiac surgery. Conclusions: We found modifiable risk factors of ventilation dependency following cardiac surgery and optimization of pre-, peri-, and postoperative factors that can reduce incidence of ventilation dependency, therefore, contribute to a better postoperative and long-term outcome.