Background: For patients requiring prolonged mechanical ventilation (PMV), weaning is difficult and mortality is very high. PMV has been defined recently, by consensus, as constituting ≥21 consecutive days of mechanical ventilation (MV) for ≥6 hours per day. This study aimed to evaluate the clinical factors predicting weaning failure in patients undergoing PMV in medical intensive care unit (ICU). Results: Among the 127 patients requiring PMV, 41 (32.3%) were successfully weaned from MV. The median age of the weaning failure group was higher than that of the weaning success group (74.0 vs. 70.0 years; P=0.003). The proportion of male patients was 58.5% in the weaning success group and 72.1% in the weaning failure group, respectively. The most common reasons for ICU admission were respiratory causes (66.1%) followed by cardiovascular causes (16.5%) in both groups. ICU mortality and in-hospital mortality rates were 55.1% and 55.9%, respectively. In the multivariate analysis, respiratory causes of ICU admission [odds ratio (OR), 3.98; 95% confidence interval (CI), 1.29-12.30; P=0.016] and a high sequential organ failure assessment (SOFA) score on day 21 of MV (OR, 1.47; 95% CI, P=0.001) were significantly associated with weaning failure in patients requiring PMV. The area under the receiver operating characteristic (ROC) curve of the SOFA score on day 21 of MV for predicting weaning failure was 0.77 (95% CI, 0.67-0.87; P=0.000).Conclusions: Respiratory causes of ICU admission and a high SOFA score on day 21 of MV could be predictive of weaning failure in patients requiring PMV.