mTORC1 signal pathway plays a role in the initiation and progression of hepatocellular carcinoma (HCC), but no relevant gene signature was developed. This research aimed to explore the potential correlation between the mTORC1 signal pathway and HCC and establish the related gene signature. HCC cases were retrieved from The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC), and Gene Expression Omnibus (GEO) databases. The genes included in mTORC1-associated signature were selected by performing univariate and multivariate Cox regression analyses and lasso regression analysis. The protein expression level of included genes was verified by The Human Protein Altas. Then, the signature was verified by survival analysis and multiple receiver operating characteristic (ROC) curve. Moreover, the correlation between signature and immune cells infiltration was investigated. Furthermore, a nomogram was established and evaluated by C-index and calibration plot. The signature was established with the six genes (ETF1, GSR, SKAP2, HSPD1, CACYBP, and PNP). Three genes (ETF1, GSR, and HSPD1) have verified their protein expression level in HCC. Under the grouping from signature, patients in the high-risk group showed worse survival than those in the low-risk group in both three datasets. The signature was found to be significantly associated with the infiltration of B cells, CD4+ T-cells, CD8+ T-cells, dendritic cells, macrophages, and neutrophils. The univariate and multivariate Cox regression analysis indicated that mTORC1-related signature could be the potential independent prognostic factor in HCC. Finally, the nomogram involving age, gender, stage, and signature has been established and verified. The mTORC1-associated gene signature established and validated in our research could be used as a potential prognostic factor in HCC. Copyright © 2020 Zhuomao Mo et al.