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Malignant mesothelioma (MM) is a highly aggressive form of cancer with limited treatment options. Although the role of NK cells has been studied in many solid tumors, the pattern of NK-cell subsets and their recognition of mesothelioma cells remain to be explored. We used RNA expression data of MM biopsies derived from the cancer genome atlas to evaluate the immune cell infiltrates. We characterized the phenotype of circulating NK and T cells of 27 MM patients before and after treatment with an anti-CTLA-4 antibody (tremelimumab). These immune cell profiles were compared to healthy controls. The RNA expression data of the MM biopsies indicated the presence of NK cells in a subgroup of patients. We demonstrated that NK cells recognize MM cell lines and that IL-15 stimulation improved NK cell-mediated lysis in vitro. Using multivariate projection models, we found that MM patients had a perturbed ratio of CD56(bright) and CD56(dim) NK subsets and increased serum concentrations of the cytokines IL-10, IL-8 and TNF-alpha. After tremelimumab treatment, the ratio between the CD56(bright) and CD56(dim) subsets shifted back towards physiological levels. Furthermore, the improved overall survival was correlated with low TIM-3(+)CD8(+) T-cell frequency, high DNAM-1(+)CD56(dim) NK-cell frequency and high expression levels of NKp46 on the CD56(dim) NK cells before and after immune checkpoint blockade. Together, our observations suggest that NK cells infiltrate MM and that they can recognize and kill mesothelioma cells. The disease is associated with distinct lymphocytes patterns, some of which correlate with prognosis or are affected by treatment with tremelimumab.