<p>AIMS: Unsuccessful weaning from ventilator after major cardiovascular procedures has been shown to be associated with increased post-operative morbidity and mortality. Our study aimed to identify predictors and clinical implications of prolonged mechanical ventilation (PMV) after left ventricular assist device (LVAD) implantation. <p>METHODS AND RESULTS: We analysed the data of patients receiving a continuous-flow LVAD in our centre from December 2010 to September 2017. PMV was defined by a duration of invasive ventilation of >7 days after LVAD implantation. Multivariable logistic regression analysis was performed for predictors of PMV. Survival was estimated by the Kaplan-Meier method. During the study period, 156 patients received a continuous-flow LVAD in our centre. Seventeen patients were excluded due to early death (<7 days), and 139 patients were enrolled in the study (mean age: 58 years; male: 84%). The median duration of mechanical ventilation post-operatively was 94 h (range: 5 to 4192 h). PMV was observed in 43% of patients. Patients on PMV were characterized by a more severe disease state at baseline, compared with the group of early extubation, as reflected by their Interagency Registry for Mechanically Assisted Circulatory Support level (Level 1-3: 72 vs. 49%, P = 0.008). Patients on PMV exhibited higher pulmonary wedge pressures (25 vs. 21 mmHg, P = 0.04), lower estimated glomerular filtration rate (53 vs. 60 mL/min/1.73 m2 , P = 0.02), lower haemoglobin (10.6 vs. 11.6 g/dL, P = 0.02), and lower platelet counts (189 vs. 240/nL, P = 0.02). Previous sternotomy was more frequent in the PMV group (32 vs. 13%, P = 0.006). Higher rates of preoperative circulatory support (30 vs. 11.4%, P = 0.006), dialysis (31.7 vs. 10.1%, P = 0.001), and invasive ventilation (35 vs. 7.6%, P < 0.001) were reported for the PMV group. Logistic regression analysis revealed that estimated glomerular filtration rate [odds ratio (OR) 0.977, confidence interval (CI) 0.955-0.999, P = 0.038], platelet count (OR 0.994, CI 0.989-0.998, P = 0.008), and previous sternotomy (OR 5.079, CI 1.672-15.427, P = 0.004) were independent predictors of PMV. PMV was accompanied by longer intensive care unit (24 vs. 4 days, P < 0.001) and hospital stay (47 vs. 32 days, P = 0.003). Survival analysis revealed a profound increase in mortality at 180-day post-implantation in the PMV group (62 vs. 10%, log-rank: P < 0.001). <p>CONCLUSIONS: Prolonged mechanical ventilation affects nearly half of patients after LVAD implantation. Previous sternotomy, renal function, and platelet counts are associated with increased risk for PMV. PMV is accompanied by decreased survival at 180-day post-implantation and longer hospitalizations.