The objective of this study was to predict postoperative liver failure and morbidity after hepatectomy for hepatocellular carcinoma (HCC) with cirrhosis. The model for end-stage liver disease (MELD) score is currently accepted as a disease severity index of cirrhotic patients awaiting liver transplantation; however, its impact on prognosis after resection of HCC on cirrhosis has never been investigated. One hundred fifty-four cirrhotic patients resected in a tertiary care setting for HCC were retrospectively analyzed. For each patient, the MELD score was calculated and related to postoperative liver failure and complications (morbidity). Hospital stay and 1-year survival was also investigated. MELD accuracy in predicting postoperative liver failure and morbidity of cirrhotic patients was assessed using receiver operating characteristic (ROC) analysis. Eleven patients (7.1%) experienced postoperative liver failure leading to death or transplantation. ROC analysis identified cirrhotic patients with a MELD score equal to or above 11 at high risk for postoperative liver failure (area under the curve [AUC] = 0.92, 95% confidence interval [CI] = 0.87-0.96; sensitivity = 82%; specificity = 89%). Forty-six patients (29.9%) developed at least 1 postoperative complication: ROC analysis identified patients with a MELD score equal to or above 9 at major risk for postoperative complications (AUC = 0.85, 95% CI = 0.78-0.89; sensitivity = 87%; specificity = 63%). Cirrhotic patients with MELD score below 9 had no postoperative liver failure and low morbidity (8.1%). In conclusion, the MELD score can accurately predict postoperative liver failure and morbidity of cirrhotic patients referred for resection of HCC and should be used to select the best candidates for hepatectomy.