Acute respiratory failure requiring mechanical ventilation is a major indicator of intensive care unit (ICU) admissions in cirrhotic patients and is an independent risk factor for ICU mortality. This retrospective study aimed to investigate the outcome and mortality risk factors in patients with liver cirrhosis (LC) who required prolonged mechanical ventilation (PMV) between 2006 and 2013 from two databases: Taiwan's National Health Insurance Research Database (NHIRD) and a hospital database. The hospital database yielded 58 LC patients (mean age: 65.3 years; men: 65.5%). The in-hospital mortality was significantly higher than in patients without LC. Based on the NHIRD database of PMV cases, patients were age-gender matched in a ratio of 1:2 for patients with and without LC. Model for End-Stage Liver Disease (MELD) score was calculated. The mortality was higher in patients with LC (19.5%) than those without LC (18.12%), though not statistically significant (p = 0.0622). Based on the hospital database, risk factor analysis revealed that patients who died had significant higher MELD score than the survivors (18.9 vs 13.7, p = 0.036) and patients with MELD score of >23 had higher risk of mortality than patients with MELD score of ≤23 (adjusted OR:9.26, 95% CI: 1.96-43.8). In conclusion, the in-hospital mortality of patients with high MELD scores who required PMV was high. MELD scores may be useful predictors of mortality in these patients.