Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality. Multiple staging systems have all been proposed to date; however, the optimal tool for stratification of prognosis is still not universally accepted. E2F targets are the essential component of cell proliferation, thus we hypothesized that a score to quantify E2F activity is expected to reflect the aggressiveness and prognosis of HCC. Methods: Total of 655 HCC patients from TCGA (The Cancer Genome Atlas) -HCC (n=358), GSE6764 (n=75), GSE76427 (n = 115), and GSE89377 (n=107) cohorts were analyzed. The score was generated using MSigDb Hallmark E2F Targets gene set using Gene Set Variation Analysis. Results: The E2F targets scores of TGCA-HCC patients showed a bimodal distribution, thus high vs. low score groups were divided by median. As expected, high E2F targets enriched all of the Hallmark cell proliferation-related gene sets; E2F targets, G2M checkpoint, MYC targets v1 and v2, and Mitotic spindle. It also enriched gene sets known to aggravate cancer, such as Glycolysis, mTORC1 signaling, DNA repair, and Unfolded protein response. E2F targets were significantly associated with histological grade, tumor size, and stage, as well as proliferation score and MKI67 expression. Furthermore, a higher E2F targets score was significantly associated with higher intra-tumoral genomic heterogeneity and homologous recombination deficiency, suggesting greater tumor aggressiveness. In agreement, E2F targets score correlated with the pathological progression from normal liver, cirrhosis, dysplasia, to early and advanced HCC consistently in two cohorts (GSE6764 and GSE89377). Further, the abundance of hepatocytes, fibroblasts, adipocytes, and lymphatic endothelial cells were all significantly less in high E2F HCC, which reflects proliferative cancer. On the other hand, there was no relationship between E2F and mutation rates or neoantigens. High E2F was associated with high infiltration of anti-cancerous immune cells; CD8, CD4 memory, and Th1 cells, however, there was no difference in cytolytic activity, and it did not enrich any of immune response-related gene sets. High E2F HCC was associated with worse disease-free (DFS), disease-specific (DSS), and overall survival (OS), and this was the case in both early (I and II) and late (III and IV) stages. A multivariate analysis revealed that the E2F targets score was an independent prognostic factor for OS (HR=1.68, 95%CI= 1.15–2.46, p = 0.007) as well as DSS (HR=1.81, 95%CI=1.27–2.59, p = 0.001) in patients with HCC. Conclusions: We found that the E2F targets score not only indicates cell proliferation, but also is associated with cancer aggressiveness and worse survival. Our findings suggest a possible future use of the E2F targets score as a prognostic biomarker in patients with HCC.