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To improve diagnostic accuracy, we developed a DNA methylation\u2010based biomarker assay capable of distinguishing PM from healthy pleura and other pleural pathologies. Using Infinium EPIC array data, we identified 744 hypermethylated CpG sites in PM as candidate biomarkers. These were validated\n                    <jats:italic>in silico<\/jats:italic>\n                    using external datasets, yielding a high mean AUC of 0.935. Clinical validation was performed using IMPRESS, a novel bisulfite\u2010free methylation detection technique that enables simultaneous analysis of thousands of CpG sites. A two\u2010step classifier approach was applied: the first model differentiated tumoral from nontumoral pleura with 89.2% sensitivity and 93.5% specificity, while the second model distinguished PM from pleural metastases with 85.2% sensitivity and 100% specificity. 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