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Introduction: Given the emergence of combination of programmed cell death protein-1 and CTLA4 pathway blockade as effective treatment options in malignant pleural mesothelioma (MPM), there is interest in the extent to which programmed death-ligand 1 (PD-L1) expression may be prognostic of clinical outcomes and predictive of response to anti–programmed death (ligand) 1 (PD-[L]1) therapies. Methods: MEDLINE and EMBASE electronic databases were searched until November 4, 2020. English-language randomized trials and observational studies that reported clinical outcomes and PD-L1 expression in adult patients (>18 or >20 y) with MPM were included. Forest plots were used to descriptively summarize clinical outcome data across studies. Results: A total of 29 publications were identified providing data on the research question. Among the studies in which anti–PD-(L)1 therapies were not specified to have been used, 63% (10 of 16) found patients with tumors expressing PD-L1 (typically >1%) to have poorer survival than those with tumors expressing lower levels of PD-L1. Among the studies in which anti–PD-(L)1 therapies were used, 83% (five of six) did not reveal an association between survival and PD-L1 tumor expression. The single study directly comparing outcomes between those treated and untreated with anti–PD-(L)1 therapies across different PD-L1 cutoffs did not identify any differences between the groups. Conclusions: The quality and consistency of the existing evidence base are currently insufficient to draw conclusions regarding a prognostic or predictive role of PD-L1 in MPM. Furthermore, high-quality studies on this topic are required to support the use of PD-L1 as a biomarker in MPM.