Renal cell carcinoma (RCC) is a heterogeneous and complex disease with almost no response to chemotherapy. Immune checkpoint inhibitors have achieved great clinical success but no interesting circulating markers of clinical use have developed so far in clear cell renal cell carcinoma (CCRCC). We investigate the diagnostic and prognostic role of plasma PD-1 (sPD-1) and PD-L1 (sPD-L1) proteins for the first time together with the immunohistochemical expression counterpart of these proteins within the tumor front and tumor center in the same sample of patients with renal cancer undergoing surgery. We also investigate these plasma and tissue markers in the population of metastatic patients according to International mRCC Database Consortium (IMDC) prognostic groups and the response to systemic therapy. The independent role of sPD-L1 as a predictor of prognosis and treatment response is demonstrated.