Background: CpG island methylator phenotype (CIMP), a common biological phenomenon characterized by a subset of concurrently methylated genes, can have an influence on the progression of multiple cancers. However, the potential mechanism of CIMP in hepatocarcinogenesis and its clinical relevance remains only partially understood. Methods: We used a methylation array from the cancer genome atlas (TCGA) to stratify HCC patients into different CIMP subtypes, and evaluated their correlation with clinical characteristics. In addition, mutation, CNV, and transcriptome profiles were also utilized to evaluate the distinctive genomic patterns correlated with CIMP. Finally, a CIMP-associated prognostic model (CPM) was trained and validated using four independent datasets. Findings: A subgroup of patients was identified as having CIMP-H, which was associated with worse OS and DFS. Gene enrichment analysis indicated that the terms "liver cancer with EPCAM up", "tumor invasiveness up", "methyltransferase complex", and "translational initiation" were enriched in CIMP-H subgroup. Notably, somatic mutation analysis indicated that CIMP-H patients presented with a higher mutation burden of BRD4, DDIAS and NOX1. Moreover, four CPM associated genes could significantly categorize patients into low-and high-risk groups in the training dataset and another 3 independent validation datasets. Finally, a nomogram incorporating a classifier based on four mRNAs, pathological M stage and CIMP status was established, which showed a favorable discriminating ability and might contribute to clinical decision-making for HCC. Interpretation: Our work highlights the potential clinical application value of CPM in predicting the overall survival of HCC patients and the mechanisms underlying the role of CIMP in hepatocarcinogenesis. Fund: This work was supported by the State Key Project on Infectious Diseases of China (2018ZX10723204-003), the National Nature Science Foundation of China (Nos. 81874065, 81500565, 81874149, 81572427, and 81401997), the Hepato-Biliary-Pancreatic Malignant Tumor Investigation Fund of Chen Xiao-ping Foundation for the Development of Science and Technology of Hubei Province (CXPJJH11800001-2018356). (c) 2019 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).