Malignant mesothelioma is a highly lethal cancer. V-set immunoregulatory receptor (VSIR, also known as V-domain Ig suppressor T-cell activation, VISTA), a negative immune checkpoint regulator, was reported to be expressed in malignant mesothelioma; however, its detailed expression pattern and clinicopathological significance have not been elucidated. We examined the expression of VSIR and CD274 and CD8 tumor-infiltrating lymphocytes in a total of 124 samples from 66 patients with malignant mesothelioma and analyzed the clinicopathological characteristics and their relationship with the immunohistochemical findings. A total of 553 non-small cell lung carcinomas were also evaluated for VSIR expression. VSIR expression was higher in epithelioid type mesothelioma (p < 0.001), whereas CD274 expression was higher in sarcomatoid type (p < 0.001). CD8 tumor-infiltrating lymphocytes were more abundant in sarcomatoid mesotheliomas (p < 0.001), VSIR-low tumors (p = 0.045), and CD274-high tumors (p < 0.001). VSIR and CD274 were differentially expressed in each histological component of the biphasic type. VSIR expression was associated with favorable survival (p = 0.008). Two patients with VSIR-high tumors had received pembrolizumab; however, they showed progressive disease. No VSIR expression was observed in tumor cells of non-small cell lung carcinomas. In conclusion, VSIR expression may define a unique class of mesothelioma, characterized by predominantly epithelioid type and favorable prognosis. VSIR expression may be used as an immunohistochemical diagnostic marker for epithelioid mesothelioma. CD274 expression was associated with sarcomatoid mesothelioma and high infiltration of CD8 lymphocytes. Because VSIR is a negative immune regulator and expressed in malignant mesothelioma, further study is warranted to investigate the therapeutic significance of VSIR blockade in this deadly cancer.