BackgroundHead and neck squamous cell carcinoma (HNSCC) is a heterogeneous tumor with diverse molecular pathological profiles. Recent studies have suggested the vital role of pyroptosis in tumor microenvironment. However, the expression patterns of pyroptosis in HPV-positive HNSCC are still unclear.MethodsUnsupervised clustering analysis was used to identify the pyroptosis patterns based on the RNA-sequencing data of 27 pyroptosis-related genes (PRGs) in HPV-positive HNSCC samples. Random forest classifier and artificial neural network were performed to screen the signature genes associated with pyroptosis, which were verified in two independent external cohorts and qRT-PCR experiment. Principal component analysis was used to develop a scoring system, namely Pyroscore.ResultsThe expression variations of 27 PRGs in HPV-positive HNSCC patients were analyzed from genomic and transcriptional domains. Two pyroptosis-related subtypes with distinct clinical outcomes, enrichment pathways and immune characteristics were identified. Next, six signature genes (GZMB, LAG3, NKG7, PRF1, GZMA and GZMH) associated with pyroptosis were selected for prognostic prediction. Further, a Pyroscore system was constructed to determine the level of pyroptosis in each patient. A low Pyroscore was featured by better survival time, increased immune cell infiltration, higher expression of immune checkpoint molecules and T cell-inflamed genes, as well as elevated mutational burden. The Pyroscore was also related to the sensitivity of chemotherapeutic agents.ConclusionsThe pyroptosis-related signature genes and Pyroscore system may be reliable predictors of prognosis and serve as mediators of immune microenvironment in patients with HPV-positive HNSCC.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13027-023-00507-w.