background: Serum high mobility group box 1 (HMGB1) serves as a diagnostic biomarker for malignant peritoneal mesothelioma (MPM) patients, yet its diagnostic significance within MPM tumor tissues remains uncertain. This study aims to elucidate the roles of HMGB1 in MPM. methods: HMGB1 expression analysis was conducted in both tumor and adjacent non-cancerous tissues collected from MPM patients. The two-year follow-up of MPM patients commenced from the diagnosis date. Inflammatory cytokine analysis was performed on these tissues, and Pearson correlation coefficient analysis was applied to examine variable relationships. In vitro assays included constructing an HMGB1 knockdown cell line, assessing cell viability, apoptosis, and inflammatory cytokine levels to delineate HMGB1's roles in MPM. results: HMGB1 overexpression was observed in MPM tumor tissues, particularly in stages III-IV. Diagnostic implications of HMGB1 for MPM were evident, augmenting its diagnostic value. HMGB1 overexpression correlated with diminished survival rates. Positive correlations existed between inflammatory cytokines and HMGB1 in MPM tumor tissues and cell lines. Suppression of HMGB1 regulated cell growth and apoptosis in MPM cell lines. conclusions: HMGB1 exhibits diagnostic potential for MPM and modulates inflammatory responses within the disease context.