Mesothelioma incidence has been analyzed in National Priority Contaminated Sites (NPCSs) to estimate the health impact of asbestos exposure on resident people. The burden of professional and environmental exposures has been identified through data of the Regional Operational Centres (CORs), made available by the Italian National Mesothelioma Registry (ReNaM). An excess of mesothelioma incidence is confirmed in sites with a known past history of direct use of asbestos, such as Balangero, Casale Monferrato, Broni, Bari-Fibronit, and in coastal areas, where shipyards, harbours and other industries that involved a wide use of asbestos are represented (e.g., Trieste, La Spezia, Venice, and Leghorn). An excess of mesothelioma has been observed in settings where the asbestos is not mentioned as contaminant in the decree that included these sites among NPCSs, such as Cengio and Saliceto in Northern Italy; Falconara Marittima and the Bacino Idrografico Fiume Sacco in the Central Italy; the Litorale Domizio Flegreo and Agro Aversano, Milazzo, and Gela in the Southern Italy. Observed excess in the various NPCSs confirms the large-scale occurrence in contaminated Italian sites of a significant amount of total mesothelioma cases observed at national level. The analysis of occupational risk in epidemiological studies with an ecological design helps in defining the contribution of different factors to the overall risk.