<jats:title>Abstract</jats:title><jats:sec> <jats:title>Background</jats:title> <jats:p>A large proportion of patients with coronavirus disease 2019 (COVID-19) develop severe respiratory failure requiring admission to the intensive care unit (ICU) and about 80% of them need mechanical ventilation (MV). These patients show great complexity due to multiple organ involvement and a dynamic evolution over time; moreover, few information is available about the risk factors that may contribute to increase the time course of mechanical ventilation.</jats:p> <jats:p>The primary objective of this study is to investigate the risk factors associated with the inability to liberate COVID-19 patients from mechanical ventilation. Due to the complex evolution of the disease, we analyzed both pulmonary variables and occurrence of non-pulmonary complications during mechanical ventilation. The secondary objective of this study was the evaluation of risk factors for ICU mortality.</jats:p> </jats:sec><jats:sec> <jats:title>Methods</jats:title> <jats:p>This multicenter prospective observational study enrolled 391 patients from fifteen COVID-19 dedicated Italian ICUs which underwent invasive mechanical ventilation for COVID-19 pneumonia. Clinical and laboratory data, ventilator parameters, occurrence of organ dysfunction, and outcome were recorded. The primary outcome measure was 28 days ventilator-free days and the liberation from MV at 28 days was studied by performing a competing risks regression model on data, according to the method of Fine and Gray; the event death was considered as a competing risk.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>Liberation from mechanical ventilation was achieved in 53.2% of the patients (208/391). Competing risks analysis, considering death as a competing event, demonstrated a decreased sub-hazard ratio for liberation from mechanical ventilation (MV) with increasing age and SOFA score at ICU admission, low values of PaO<jats:sub>2</jats:sub>/FiO<jats:sub>2</jats:sub> ratio during the first 5 days of MV, respiratory system compliance (C<jats:sub>RS</jats:sub>) lower than 40 mL/cmH<jats:sub>2</jats:sub>O during the first 5 days of MV, need for renal replacement therapy (RRT), late-onset ventilator-associated pneumonia (VAP), and cardiovascular complications.</jats:p> <jats:p>ICU mortality during the observation period was 36.1% (141/391). Similar results were obtained by the multivariate logistic regression analysis using mortality as a dependent variable.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusions</jats:title> <jats:p>Age, SOFA score at ICU admission, C<jats:sub>RS</jats:sub>, PaO<jats:sub>2</jats:sub>/FiO<jats:sub>2</jats:sub>, renal and cardiovascular complications, and late-onset VAP were all independent risk factors for prolonged mechanical ventilation in patients with COVID-19.</jats:p> </jats:sec><jats:sec> <jats:title>Trial registration</jats:title> <jats:p><jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="https://clinicaltrials.gov/ct2/show/NCT04411459">NCT04411459</jats:ext-link></jats:p> </jats:sec>