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Background: To investigate the effect of extubation in the operating room (OR) on mechanical ventilation-related adverse outcomes in patients who undergo liver transplantation. Methods: Patients who underwent liver transplantation between January 2016 and December 2019 were included. According to the timing of extubation, patients were divided into OR extubation group and intensive care unit (ICU) extubation group. The propensity score was used to match OR extubation group and ICU extubation group at a 1:2 ratio by demographical and clinical covariates. The primary outcome was a composite of mechanical ventilation-related adverse outcomes, including 30-day all-cause mortality, in-hospital acute kidney injury (stage 2 or 3), and in-hospital moderate to severe pulmonary complications. Secondary outcomes included in-hospital moderate to severe infectious complications, unplanned reintubation rates, ICU and postoperative hospital lengths of stay, and total hospital cost. Results: A total of 438 patients were enrolled. After propensity score matching, 94 patients were in OR extubation group and 148 patients were in ICU extubation group. Incidence of the composite mechanical ventilation-related adverse outcomes was significantly lower in OR extubation group than ICU extubation group, even after adjusting for confounding factors (19.1% vs. 31.8%; Odds Ratio, 0.509; 95% Confidence Index [CI], 0.274-0.946; P=0.031). The duration of ICU stay was much shorter in OR extubation group than ICU extubation group (median 4, Interquartile range [IQR] (3 ~ 6) vs. median 6, IQR (4 ~ 8); P<0.001). Meanwhile, extubation in the OR led to a significant reduction of total hospital cost compared with extubation in the ICU (median 3.9, IQR (3.5 ~ 4.6) 10000 US dollars vs. median 4.1, IQR (3.8 ~ 5.1) 10000 US dollars; P=0.021). However, there were no statistically significant differences in moderate to severe infectious complications, unplanned reintubation rates, and the length of postoperative hospital stay between groups. Conclusions: Among patients who underwent liver transplantation, extubation in the OR compared with extubation in the ICU, significantly reduced the primary composite outcome of 30-day all-cause mortality, in-hospital acute kidney injury (stage 2 or 3), or in-hospital moderate to severe pulmonary complications. Trial registration: The trial was registered at www.clinicaltrials.gov with registration number NCT04261816. Retrospectively registered on 1st February 2020. [ABSTRACT FROM AUTHOR]