Mitochondrially targeted tamoxifen (MitoTam) has recently undergone phase 1/1b clinical trial in patients with various solid tumors. Since patients with clear cell renal carcinoma showed the highest response of the tested diagnoses, we studied the effect of MitoTam on renal cancer in vitro and in vivo to reveal its mechanism of action in more detail and to better understand its benefit for patients. Using primarily the murine RenCa renal cancer cell line and the derived syngeneic mouse tumor model, we studied mechanism of MitoTam toxicity including the mode of death, the role of mitochondria in the effects of the agent, and its efficacy in suppressing syngeneic tumors in mice alone and in combination with the immune checkpoint inhibitors (ICIs), monoclonal antibodies blocking PD-1 and PD-L1. Our findings show a complex effect of MitoTam on mitochondrial function and integrity of renal cancer cells. The agent inhibits complex I-dependent respiration and lowers mitochondrial potential, which results in activation of necroptosis as the major mode of cell death. As a consequence, MitoTam reduces growth of renal tumors as well as metastatic spread of tumor cells via specific targeting of malignant tissue in a mouse model. Moreover, combination of MitoTam with immunotherapy to enhance its anti-cancer efficacy shows significantly increased suppression of tumor growth as well as increased survival of experimental animals compared to single agent treatment. Our data provide a mechanistic rationale for testing of both mono and/or combinatorial therapy with MitoTam plus ICIs in renal carcinomas in Phase 2 trial.