FOXM1 (Forkhead box M1) is a key regulator of tumorigenesis. Previous studies demonstrated that FOXM1 overexpression was strongly correlated with poor prognosis in various cancers, including hepatocellular carcinoma (HCC). In this study, we examined an association between the gene expression signature of FOXM1 and HCC patient outcome. The co-expressed gene set of FOXM1, which is significantly associated with the prognosis of HCC patients, was identified by analyzing the gene expression profiles of 100 patients with HCC, and this gene set was validated in two independent HCC patient cohorts (n=573). In multivariate analysis, the co-expressed gene set of FOXM1 was the most significant prognostic factor for overall survival in patients with HCC (hazard ratio=1.706, 95% confidence intervals=1.176-2.475, P=0.005). We also analyzed different types of cancer, including pancreatic adenocarcinoma, lung adenocarcinoma, breast carcinoma and bladder urothelial carcinoma, to verify the association between the co-expressed gene set of FOXM1 and patient prognosis, and we found a consistent prognostic significance, regardless of tumor type. Finally, we identified a putative signaling pathway in which miR-34a acts as an upstream regulator of the FOXM1-MYC signaling network; this pathway may be ultimately responsible for the poor prognosis of HCC patients. The prognostic subgroups defined by the gene expression signature of FOXM1 could help predict high-risk patients and may guide selection of the best treatment strategy.