Progesterone receptor membrane component 1 (PGRMC1) and Na+/K+‑ATPase α1 subunit (ATP1A1) are two proteins associated with the clinical prognosis of renal cell carcinoma (RCC) and RCC cell proliferation. However, the two proteins have been previously studied independently, and their combined influence on the clinical outcome of RCC remains unclear. The present study suggests that the combined expression levels of PGRMC1 and ATP1A1 (PGRMC1/ATP1A1) are associated with the clinical prognosis of RCC patients. RCC patients with low PGRMC1/positive ATP1A1 levels exhibited the best overall survival (OS) outcomes (103.08±1.85 months). The high PGRMC1/negative ATP1A1 group demonstrated the worst prognosis (73.1±8.87 months). The low PGRMC1/positive ATP1A1 group had the highest 7‑year OS rate (92.3%). The high PGRMC1/negative ATP1A1 group had the lowest 7‑year OS rate (46.7%). Although PGRMC1 and ATP1A1 both act on AKT phosphorylation in RCC cells, their expression levels are independent of each other. Moreover, the synergistic suppressive roles of PGRMC1 downregulation combined with ATP1A1 upregulation exhibit more efficient tumor inhibition potentials on RCC cells. Therefore, combined assessment of the two biomarkers (PGRMC1/ATP1A1) shows enhanced prognostic ability for RCC.