INTRODUCTION Malignant pleural mesothelioma (MPM) is a rare, highly aggressive, relatively chemo- and radio-resistant malignancy with limited therapeutic options. Our objective was to investigate the prevalence of PD-L1 and the characteristics of immune environment in this disease. METHODS A total of 99 archival tumors from advanced stage MPM were immunohistochemically tested in parallel for PD-L1 in two different laboratories; and 87 of these were profiled for immune gene expression profiling by NanoString analysis for 800 genes. A prior study on the same samples indicated a low mutational load with a complex mutational landscape of genetic variations more frequently associated with the p53/DNA repair and Pi3K pathways. RESULTS PD-L1 expression was found in 16% of the MPM tumor samples, either in the tumor cells (TC) or the infiltrating immune cells. Gene expression analysis suggested that, MPM is an inflamed tumor type and can be classified into three different subgroups, based on the different expression profiles of immune-related genes, of which, two groups showed varying degrees of expression of immune related genes. Overall, these molecular findings suggest that these sub-groups of MPM associated with PD-L1 positivity, and expression of immune related genes representing about 60% of MPM, represents a candidate subtype that may respond to cancer immunotherapy. CONCLUSION These data suggest that 60% of MPM patients characterized by either PD-L1 expression or an inflamed status present an attractive candidate for cancer immunotherapeutic options.