<p>Hyponatremia is the most common electrolyte disorder in cancer patients and is associated with a worse outcome. This finding has also been reported in patients with metastatic renal cell carcinoma (mRCC). We have previously demonstrated that low extracellular sodium concentrations ([Na⁺]) increase cell proliferation and invasion in several human cancer cell lines. The aim of the present study was to evaluate in vitro the effects of mild [Na⁺] alterations on two mRCC cell lines, ACHN and Caki-1. After growth in reduced extracellular [Na⁺], we observed that even mild reductions of [Na⁺] significantly enhanced different key cancer cell features, including proliferation, invasion and migration. Furthermore, we observed a reduction in reactive oxygen species (ROS) levels in low [Na⁺], with a significant increase of the antioxidant Nrf2/HMOX-1 pathway. Since an excess of ROS causes cell death, this finding clarifies the role of Nrf2/HMOX-1 in maintaining the balance between oxidant and antioxidant species in the tumor environment, promoting cell survival. Although further clinical studies are needed, aiming for instance to determine whether serum [Na⁺] correction improves the outcome of patients with mRCC, our findings suggest that attention should be deserved to serum [Na⁺] in this setting.</p>