Objective: The aim of this study was to evaluate the usefulness of the Mac-2 binding protein glycosylation isomer (M2BPGi) for the prediction of post-hepatectomy liver failure (PHLF) in hepatocellular carcinoma (HCC) patients. Summary Background Data: M2BPGi is a novel serum marker of liver fibrosis. The usefulness of M2BPGi for the prediction of PHLF has not been evaluated. Methods: Clinicopathological data were analyzed in 138 HCC patients who underwent liver resection between August 2011 and November 2014. PHLF was evaluated according to the definition of the International Study Group of Liver Surgery. Performance of preoperative parameters in predicting PHLF was determined using receiver operating characteristic (ROC) analysis. Results: Serum M2BPGi level correlated with the METAVIR fibrosis score. M2BPGi levels of hepatitis C virus (HCV)-positive patients were significantly higher than those of HCV-negative patients, even in the same fibrosis stage. PHLF >= Grade B developed in 19 patients (13.8%). The area under the ROC curve (AUROC) of M2BPGi for the prediction of PHLF >= Grade B was 0.71. In multivariate analysis, M2BPGi [odds ratio (OR): 2.08, 95% confidence interval (CI) 1.28-3.55], platelet count (OR: 0.39, 95% CI 0.18-0.80), and resection rate (OR: 2.71, 95% CI 1.46-5.40) were the significant factors associated with PHLF >= Grade B. The AUROC of the PHLF index defined by these factors was 0.81. Notably, in patients with HCVinfection, the predictive ability of M2BPGi for PHLF (AUROC 0.85) was the best among the preoperative parameters. Conclusions: M2BPGi is a useful predictor of PHLF, especially in patients with HCV infection.