Purpose: We investigated whether COVID-19 patients on mechanical ventilation (MV) had a different extubation outcome compared to non-COVID-19 patients while identifying predictive factors of extubation failure in the former. Methods: A retrospective, single-center, and observational study was done on 216 COVID-19 patients admitted to an intensive care unit (ICU) between March 2020 and March 2021, aged ≥ 18 years, in use of invasive MV for more than 24 h, which progressed to weaning. The primary outcome that was evaluated was extubation failure during ICU stay. A statistical analysis was performed to evaluate the association of patient characteristics with extubation outcome, and a Poisson regression model determined the predictive value. Results: Seventy-seven patients were extubated; the mean age was 57.2 years, 52.5% were male, and their mean APACHE II score at admission was 17.8. On average, MV duration until extubation was 8.7 ± 3.7 days, with 14.9 ± 10.1 days of ICU stay and 24.6 ± 14.0 days with COVID-19 symptoms. The rate of extubation failure (ie, the patient had to be reintubated during their ICU stay) was 22.1% (n = 17), while extubation was successful in 77.9% (n = 60) of cases. Failure was observed in only 7.8% of cases when evaluated 48 hours after extubation. The mean reintubation time was 4.28 days. After adjusting the analysis for age, sex, during of symptoms, days under MV, dialysis, and PaO2/FiO2 ratio, some parameters independently predicted extubation failure: age ≥ 66 years (APR = 5.12 [1.35-19.46]; p = 0.016), ≥ 31 days of symptoms (APR = 5.45 [0.48-62.19]; p = 0.016), and need for dialysis (APR = 5.10 [2.00-13.00]; p = 0.001), while a PaO2/FiO2 ratio >300 decreased the probability of extubation failure (APR = 0.14 [0.04-0.55]; p = 0.005). The presence of three predictors (ie, age ≥ 66 years, time of symptoms ≥ 31 days, need of dialysis, and PaO2/FiO2 ratio < 200) increased the risk of extubation failure by a factor of 23.0 (95% CI, 3.34-158.5). Conclusion: COVID-19 patients had an extubation failure risk that was almost three times higher than non-COVID-19 patients, with the extubation of the former being delayed compared to the latter. Furthermore, an age ≥ 66 years, time of symptoms ≥ 31 days, need of dialysis, and PaO2/FiO2 ratio > 200 were independent predictors for extubation failure, and the presence of three of these characteristics increased the risk of failure by a factor of 23.0.