Accumulating evidence highlighted the important roles of platelets in the prognosis and progression of various tumors. Nevertheless, the role of platelet-related genes (PRGs) in HCC remains limited. In this work, 92 differentially expressed PRGs were described in HCC using TCGA and ICGC databases. Then, based on the different expressions of PRGs, we explored two subtypes and developed the PRGs prognostic signature in HCC. The PRGs signature was an independent prognosis factor associated with immune cell infiltration in HCC. Furthermore, two external validation sets verified the expression and prognosis of the PRGs signature gene in HCC. Finally, scRNA-seq analysis demonstrated that the signature genes (CENPE and KIF2C) were mainly expressed in cycling T cells and prolif-TAMs. Enrichment analysis showed that CENPE and KIF2C regulated the cell cycle and p53 pathways in these cells. In conclusion, this study builds the PRGs-related risk signature of HCC and reveals the potential mechanism by which these signature genes regulate the immune microenvironment in HCC.