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Objective Using a nationwide case-control design, we examined the association between occupational asbestos exposure and peritoneal mesothelioma (PM) risk in the general population in Italy.Material and Methods PM cases diagnosed in 2000-2021 and their life-time occupational history collected through interview were extracted from the National Mesothelioma Registry. Controls were 3,045 from three case-control studies performed in six regions in 2002-2004 (2,116 population controls) and 2012-2016 (718 population and 211 hospital controls). Individual exposure assignment was based on a quantitative job-exposure matrix (SYN-JEM). Expert-based exposure assignment was available for cases and controls for the period 2011-2021. Odds ratios (OR) and 90% confidence intervals (CI) were estimated using logistic regression models adjusted for geographical area (North-East, North-West, Centre, South) or region, gender, period (2000-2010, 2011-2021), and age.Results In a complete analysis (1,591 cases in all years and areas, 2000-2021) OR for ever exposure to asbestos was 3.66 (CI: 3.21-4.18, 45.4% cases and 27.8% controls exposed); and the OR for cumulative exposure was 2.87 (CI: 2.57-3.20) per natural log transformed fibres/mL-years. In analyses restricted to 290 cases enrolled in the same years (2002-2004, 2012-2016) and regions of controls, ORs were very similar: 3.35 (CI: 2.57-4.37, 43.8% cases exposed) and 2.74 (CI: 2.24-3.36) per ln(fibres/mL-years). ORs for ever exposed to asbestos based on expert assessment were 4.32 (CI: 3.50-5.34, 53.9% cases and 26.4% controls exposed) in complete analysis (778 cases, 2011-2021) and 6.35 (CI: 4.58-8.81, 57.1% cases exposed) in restricted analysis (245 cases, 2012-2016).Conclusion In a nationwide population-based study we found clear positive associations between PM and occupational asbestos exposure using different exposure metrics. These results are relevant for compensation of affected individuals independently of the industrial sectors in which they were exposed.