Metabolic reprogramming has been proven to be a hallmark of cancer. The pathogenic factors involved in Hepatocellular carcinoma (HCC) lead to an abnormal lipid metabolism that facilitates the malignant transformation of liver cells . However, the association between lipid metabolism and the prognosis of HCC has not been systematically delineated. In this study, the training set comprised 221 patients from The Cancer Genome Atlas (TCGA) based on the gene expression details, whereas 230 patients within the International Cancer Genome Consortium (ICGC) comprised the validation set. Ten lipid metabolism-related risk genes were screened; they were found to be significantly related to the prognosis of HCC. The risk score was calculated based on ten screened lipid metabolism-related risk genes and was confirmed to be an independent prognostic factor for HCC even when excluding clinical features. Therefore, a novel nomogram integrating the risk score and other proven clinical attributes was constructed. The results of the area under the receiver operating characteristics curve (AUC), C index, and calibration plot supported the better predictive capacity of the nomogram over others. Treatment with metformin significantly positively affected the expression of four out of ten genes; this was beneficial to longer overall survival. The results provide a new insight into accurate prognostic prediction, as well as understanding the carcinogenesis and process of HCC .