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Malignant Pleural Mesothelioma (MPM) is an aggressive cancer caused by occupational, environmental and indirect exposure to asbestos, material that some countries have already prohibited. Survival is less than 1 year. Diagnosis is currently a challenge and the search for early, single or combined diagnostic biomarkers continues to be performed on non-invasive samples.A case-control study was conducted in 166 cases and 394 controls recruited from 2007–2016 at the Mexican Social Security Institute. Men and Women were included. The plasma concentration of mesothelin, calretinin and megakaryocyte potentiating factor (MPF) was determined by Enzyme-linked ImmunoSorbent Assay (ELISA) in each sample. Each participant has general data, socio-economic, occupational exposure, environmental, etc. Data were analysed using STATA.The median of mesothelin in cases and controls was 2.25 and 0.55 nM/ml respectively; For MPF of 50.80 and 17.13 ng/ml and for calretinin of 1.05 and 0.14 ng/ml. Mesothelin had a sensitivity of 80.12% and specificity of 91.12% (AUC=0.9175); MPF with 78.18% and 88.78% (AUC=0.9009) and calretinin with 79.88% and 81.68% (AUC=0.8791), respectively.Mesothelin is the most promising molecule to be used as a diagnostic biomarker of (MPM) because it offers better specificity alone or in combination with another biomarker. However, it will be necessary searching for other molecular levels of biomarkers that offer, together with mesothelin, the capability to increase the sensitivity and specificity of a non-invasive diagnostic method.