Background: Recent clinical studies using immune checkpoint inhibitors in mesothelioma (MM) have shown promise in shifting treatment paradigms. However, the immune environment and targets of these treatments such as program death receptor 1 (PD-1) and its ligand PD-L1 have not been well characterised in MM. In a large cohort of patients, we investigated PD-L1 expression, the surrounding immune infiltrate and genome-wide copy number status and correlated these parameters to clinicopathological features. Methods: Tissue microarrays (TMA) were constructed and stained with PD-L1 (E1L3N, CST, Massachusetts), CD4, CD8 and Foxp3 antibodies. PD-L1 positivity (PD-L1+) was defined as > 5% membranous staining regardless of intensity and high positive as > 50%. Genomic DNA obtained from tumour of a representative subset (68 patients) was used for genome-wide copy number analysis (CNA) using Affymetrix’s OncoScan platform. Percent Genome Aberrated (PGA) was computed for each sample. Results: Amongst 329 patients evaluated, the median age was 67 years. Most were male 274(83.2%). Epithelioid histology (N = 203; 62.9%) was the commonest. PD-L1+ was seen in 41.7% with high positivity in 9.6%. PD-L1+ correlated with non–epitheloid histology (P = < 0.0001) and increased infiltration with CD4, CD8 and FOXP3 lymphocytes. High PD-L1 expression correlated with worse prognosis (HR = 2.37; 95%CI: 1.57-3.56; P = < 0.0001) on univariate analysis. On multivariate analysis histology, stage, Neutrophil-Lymphocyte ratio (NLR) and ECOG status were found to be independently associated with survival, but not PD-L1+. PD-L1 gene (CD274) copy number gains were seen in seven (11.2%) of patients but did not correlate with PD-L1 expression. Higher PGA was seen in epithelioid histology, was not associated with PD-L1 expression but trended towards poorer survival (HR = 1.5; 95%CI: 0.89-2.68; P = 0.14). Conclusions: High PD-L1 expression was associated with non-epithelioid MM, poor clinical outcome and increased immunological infiltrates. Interestingly, increased genomic alterations did not correlate with PD-L1 expression but was associated with poorer survival.