INTRODUCTION: Pleural Mesothelioma (PM) is a rare and aggressive cancer where prognostic assessment is crucial. Traditional prognostic scores such as the European Organisation for Research and Treatment of Cancer (EORTC) and the Cancer and Leukaemia Group B (CALGB) have limitations, particularly in reflecting contemporary treatments and demographic diversities, while more recent scores often include novel biomarkers, not widely available and validated. Our goal is to create an effective prognostic score for PM using readily available baseline data. METHODS: A retrospective cohort study at two Mexican cancer centers included patients with unresectable PM treated with first-line chemotherapy from 2010 to 2023. Baseline variables' associations with overall survival (OS) and progression-free survival (PFS) were analyzed. Prognostic variables from univariate and multivariate analyses formed a baseline risk score. The score's OS prediction was compared to standard CALGB and EORTC scores using ROC curves and Kaplan-Meier analysis. RESULTS: Among 262 patients (69.1% male, 80.5% epithelioid histology), we developed a 0-7 point PLECH score based on five variables: Platelet count (P: +2), high LDH (L: +1), ECOG ≥ 2 (E: +1), Chest pain at diagnosis (C: +2), and non-epithelioid Histology (H: +1). The score had an AUC of 0.70 for predicting 1-year OS, outperforming CALGB (0.60) and EORTC (0.57) scores, with an optimal cut-off of 2.5 (sensitivity 75%, specificity 55%). High scores (≥3) indicated worse OS (12.3 vs. 20.1 months
p<
0.001) and PFS (6.4 vs. 11.3 months
p<
0.001). CONCLUSION: The PLECH score, developed from a substantial Latin-American cohort, is a simple and effective prognostic tool for PM patients, outperforming traditional scores. It identifies a high-risk group potentially better suited to alternative treatments.