<p>Primary hepatic adenosquamous carcinoma (PHASC) is rare and information about its pathogenesis is limited. This case report uses proteomics to explore its biological characteristics, protein changes, and possible pathogenesis. A 36-year-old woman was admitted to our hospital in Guizhou Province in China in May 2024 with a 10-day history of upper abdominal pain and fever. She underwent liver plain contrast-enhanced computed tomography (CT), magnetic resonance imaging, liver puncture biopsy, and positron emission tomography CT (PET-CT). A preliminary diagnosis of hepatic squamous cell carcinoma was made based on the imaging, pathology and immunochemistry findings. Owing to the patient’s recurrent high fever, the tumor was resected. The postoperative pathological diagnosis confirmed the diagnosis as PHASC. Proteomic analysis revealed 291 significantly upregulated and 287 significantly downregulated proteins in the cancer tissue. Gene Ontology (GO) enrichment analysis revealed that the significantly differentially expressed proteins were mainly involved in processes such as regulation of inflammatory response, single strand break repair, and cilium or flagellum-dependent cell motility. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway prediction revealed that these proteins included “Cell adhesion molecules” and “Motor proteins,” and were involved in pathways such as the “Apelin signaling pathway,” and “Autophagy.” The patient has been followed up for more than 1 year since discharge, with no sign of recurrence.This report provides new insights into the pathogenesis of PHASC.</p>