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Objectives To investigate potential germline mutations that may confer susceptibility to pleural mesothelioma (PM), with the goal of identifying individuals at increased risk despite similar levels of occupational or environmental asbestos exposure. This objective aims to shed light on the pathogenesis of PM, a rare and aggressive malignancy primarily linked to asbestos exposure and still lacking effective therapeutic options.Material and Methods We conducted a case-control study involving two groups: (1) PM patients (n=16) with confirmed asbestos-related exposure, and (2) asbestos-exposed individuals (controls, n=32) who did not develop PM after a minimum follow-up period of 20 years. All participants were residents of the Pavia province (Lombardy, Italy), a region with elevated PM incidence due to both occupational and environmental asbestos exposure. Germline DNA samples underwent targeted Next-Generation Sequencing (NGS) using a gene panel focused on pathways related to inflammatory response, drug metabolism, and cancer susceptibility. Bioinformatic analyses were employed to identify and annotate relevant genetic variants.Results Germline variants were identified in several cancer susceptibility genes, including FBXW7 (75% of cases vs. 50% of controls), ATM (56% vs. 41%), BRCA2 (19% vs. 41%), PBRM1 (12% vs. 34%), and FAT1 (12.5% vs. 25%). Notably, a deletion in FBXW7 was observed in 62.5% of PM cases compared to 41% of controls.Conclusion Our preliminary findings highlight specific germline mutations that may contribute to increased susceptibility to PM following asbestos exposure. These results support the hypothesis that genetic predisposition plays a role in PM development alongside environmental and occupational risk factors. Further studies are warranted to validate these observations and explore their clinical relevance.