Samples and methods: Sequencing data were collected from The Cancer Genome Atlas database, The International Cancer Genome Consortium (ICGC), and The Integrative Molecular Database of Hepatocellular Carcinoma (HCCDB). First, we investigated the expression levels and copy number variations (CNVs) of 56 pyroptosis genes in HCC and pan-cancer. Next, we identified 614 genes related to 56 pyroptosis-associated genes at the expression, mutation, and CNVs levels. Pathway enrichment analysis of 614 genes in the Hallmark, KEGG, and Reactome databases yielded a total of 253 significant signaling pathways. The pyroptosis-regulated genes (PRGs) comprised 108 genes that were derived from the top 20 signaling pathways, of which 57 genes had prognostic value in HCC. The least absolute shrinkage and selection operator (LASSO) analysis was performed to screen for PRGs with prognostic values. Ultimately, we constructed a risk score model with seven PRGs to predict HCC prognosis and validated its predictive value in three independent HCC cohorts. Risk scores were used to illustrate receiver operating characteristic (ROC) curves predicting 1, 3, and 5-years overall survival (OS). Single-sample gene set enrichment analysis (ssGSEA), was performed to study 28 types of immune cells infiltrated in HCC. The relationship between the risk signature and six immune checkpoint genes and immunotherapy was analyzed.