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Introduction: Prolonged mechanical ventilation (PMV) occurs in approximately 10% of patients receiving mechanical ventilation in the intensive care unit (ICU) and is associated with high rates of complications and mortality. Previous studies showed that ventilator parameters are a valuable tool for predicting weaning outcomes. This study aimed to investigate the association between ventilator parameters and weaning outcome in PMV patients. Methods: This retrospective cohort study was conducted at a single center in Taiwan from 2019 to 2022. Intubated patients who received mechanical ventilation for at least 21 days and met the weaning criteria (PEEP ≤ 8 cmH2O and FiO2 ≤ 40%) were enrolled after transfer from the ICU to the RCC. Ventilator parameters, APACHE II scores, and laboratory data were collected at RCC admission to evaluate the associations and develop a predictive model for successful weaning. Successful weaning was defined as no ventilator use for more than five consecutive days. Results: A total of 250 intubated patients with PMV were included. After excluding 26 patients with incomplete data, 224 patients were analyzed. The successful weaning (SW) rate in the RCC was 67.41%. The SW group (n=151) had significantly lower peak inspiratory pressure (PIP) than the failed group (n=73) (17 cmH2O [15-19] vs. 18 cm H2O [17-22], p < 0.001) at the time of admission to the RCC. Mechanical power (MP) was also significantly lower in the SW group (8.85 J/min vs. 10.02 J/min, p=0.044). Length of RCC stay and duration of ventilation were significantly longer in higher PIP group. PIP at RCC admission showed a higher area under the receiver operating characteristic curve than the rapid shallow breathing index (0.647 vs. 0.516). Lower PIP was significantly associated with weaning success (AOR = 0.863, 95% CI = 0.782-0.952, p = 0.003) after adjusting for APACHE II scores and albumin levels. Conclusions: In patients with PMV, lower PIP was independently associated with successful weaning. As a routinely measured ventilator parameter, PIP may serve as screening tool for weaning potential at the time of RCC admission.