Aim: To identify predictors of weaning failure from invasive mechanical ventilation (IMV) in patients with COVID-19. Methods: Data was obtained from medical records: anthropometric data, smoking history, symptoms, comorbidities, pulmonary damage, IMV parameters, ventilatory mechanics, time on IMV, hospital and intensive care unit (ICU) length of stay, day of discharge or death. All individuals with COVID-19 admitted between March 2020 and April 2021, aged ?18 years and who required IMV were included. They were separated into two groups: weaning success (WS) and failure (WF). Success was defined as orotracheal prosthesis removal without the need for reintubation within 48 hours or, for tracheostomized patients, continuous nebulization for a period ?48 hours. Results: 1.000 individuals were included, among them 229 met the criteria for weaning and were analyzed (WS n=180, 96 men; WF n=49, 33 men). Individuals in the WS group were younger (WS 55[43-63] vs WF 62[52-70] years; p<0.0001), besides spending less time in the ICU (WS 17[10-27] vs WF 31[17-47] days; p<0.0001) and on IMV (WS 13 [7-20] vs WF 28 [18-40] days; p<0.0001). Age (OR[95%CI]1.070[1.023-1.119]), length of hospital stay (OR[95%CI] 0.939[0.888?0.993]), time on IMV (OR[95%CI]1.147[1.066?1.236]) and driving pressure (OR[95%CI]4.215[1.004?17.703]) were predictors of weaning failure, regardless of gender and comorbidities. The proportion of individuals who died was higher in the WF group (WF 69% vs WS 24%; p<0.0001). Conclusion: Individuals with COVID-19 who are older, present compromised ventilatory mechanics and remain on IMV for a longer period are more likely to fail in ventilatory weaning.