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Purpose: Pleural mesothelioma (PM) is an aggressive tumor still considered incurable, in part due to the lack of predictive biomarkers. Little is known about the clinical implications of molecular alterations in resectable PM tissues and blood. Here, we characterized genetic alterations to identify prognostic and predictive biomarkers in patients with resected PM., Experimental Design: Targeted next-generation sequencing was performed in retrospective pleural tumor tissue and paired plasma samples from stage IB-IIIB resected PM. Association between prognosis and presence of specific mutations was validated in silico., Results: Thirty PM tissues and paired blood samples from 12 patients were analyzed. High tissue tumor mutational burden (TMB) (>10 mutations/Mb), tissue median minor allele frequency (MAF) (>9 mutations/Mb), and blood TMB (>6 mutations/Mb), tissue KMT2C, PBRM1, PKHD1,EPHB1 and blood LIFR mutations correlated with longer disease-free survival and/or overall survival. High concordance (>80%) between tissue and blood was found for some mutations., Conclusions: Tissue TMB and MAF, blood TMB, and specific mutations correlated with outcomes in patients with resected PM and should be further studied to validate their role as prognostic biomarkers and potentially predictive factors for combinations with immune-checkpoint inhibitors. This suggest that molecular profiling could identify longer survivors in patients with resected PM., Competing Interests: Declaration of Competing Interest Umberto Malapelle has received personal fees (as consultant and/or speaker bureau) from Boehringer Ingelheim, Roche, MSD, Amgen, Thermo Fisher Scientifics, Eli Lilly, Diaceutics, GSK, Merck, AstraZeneca, Janssen, Diatech, Novartis and Hedera unrelated to the current work. Pasquale Pisapia has received personal fees as speaker bureau from Novartis, for work performed outside of the current study. Giancarlo Troncone reports personal fees (as speaker bureau or advisor) from Roche, MSD, Pfizer, Boehringer Ingelheim, Eli Lilly, BMS, GSK, Menarini, AstraZeneca, Amgen, and Bayer unrelated to the current work. Alessandro Russo reports advisory board role/consultancy from AstraZeneca, MSD, Novartis, Pfizer, BMS, Roche, and Amgen unrelated to the current work. Andres F. Cardona discloses financial research support from Merck Sharp & Dohme, Boehringer Ingelheim, Roche, Bristol‐Myers Squibb, Foundation Medicine, Roche Diagnostics, Thermo Fisher, Broad Institute, BioNTech, Amgen, Flatiron Health, Teva Pharma, Rochem Biocare, Bayer, INQBox and The Foundation for Clinical and Applied Cancer Research – FICMAC; advisor role to EISAI, Merck Serono, Jannsen Pharmaceutical, Merck Sharp & Dohme, Boehringer Ingelheim, Roche, Bristol‐Myers Squibb, Pfizer, Novartis, Celldex Therapeutics, Foundation Medicine, Eli Lilly, Guardant Health, Illumina, and Foundation for Clinical and Applied Cancer Research – FICMAC outside the submitted work. Marzia Del Re has received research grants from Astellas and AstraZeneca, consulting fees from Janssen, AstraZeneca, Astellas, discloses speaker bureau role for AstraZeneca, Astellas, Janssen, Novartis, Roche, Daiicho Sankyo, Takeda, advisory board role for Novartis, Roche, and Amgen outside the submitted work. Ashutosh Sachdeva reports consulting fees from AMBU and MERIT, advisory board role for AMBU not related to the submitted work. Fred R. Hirsch reports advisory boards consultancy for Bristol‐Myers Squibb, AstraZeneca/Daiichi, Sanofi/Regeneron, Novartis, Amgen, OncoCyte, Genentech, and Nectin Therapeutics unrelated to the current work. Christian Rolfo is a speaker for Merck Sharp and Dohme, AstraZeneca, COR2ED, Daiichi Sankyo, Physicians Education Resource, and Roche (CH); has research collaborations (nonfinancial support) with Guardant Health; advisory board activity: Archer, Inivata, Bayer U.C. LLC, Boston pharmaceutical, CEA, MD Serono, General Dynamics, MedStar, Novartis, Sanofi Genzyme‐Regeneron. Provides expert testimony to Intellisphere, scientific board for Imagene, and is a coordinating PI for MD Serono Global PI LUNG itrapid@ 024 trial. Research grant from LCRF‐Pfizer unrelated to the current work. The other authors declare no competing interest., (Copyright © 2023. Published by Elsevier Ltd.)