PURPOSE Combination of immune checkpoint inhibitors with chemotherapy is under investigation for cancer treatment. EXPERIMENTAL DESIGN We studied the rationale of such a combination for treating mesothelioma, a disease with limited treatment options. RESULTS The combination of gemcitabine and immune checkpoint inhibitors outperformed immunotherapy alone with regard to tumor control and survival in a pre-clinical mesothelioma model; however, the addition of dexamethasone to gemcitabine and immune checkpoint inhibitors nullified the synergistic clinical response. Further, treatment with gemcitabine plus anti-PD-1 resulted in an objective clinical response in two mesothelioma patients, who were resistant to gemcitabine or anti-PD-1 as monotherapy. CONCLUSION Thus, treatment of mesothelioma with a combination of gemcitabine with immune checkpoint inhibitors is feasible and results in synergistic clinical response compared to single treatment in the absence of steroids.