Renal cell carcinoma (RCC) is an immunogenic and proangiogenic cancer. Although antivascular endothelial growth factor (VEGF) therapies achieve impressive responses in some patients, many tumors eventually develop resistance to such therapy. The B7 family molecules such as CTLA-4, PD-1, and PD-L1 are pivotal players in immune checkpoints that positively or negatively regulate various immune responses. Recently, immunotherapy based on blocking immune checkpoints with anti-CTLA4, anti-PD-1, or anti-PD-L1 antibodies has been proposed as a potential new approach to the treatment of metastatic RCC. Higher expression of PD-L1 and B7-H4 in the tumors is associated with a poor prognosis in RCCs, however, the clinical impact of serum levels of B7 family molecules has not been elucidated in patients with metastatic RCCs receiving VEGF-targeted agents. We assessed the preoperative serum levels of B7 family molecules, including CD80, CD86, PD-1, PD-L1, B7-H3, B7-H4, and CTLA-4, and CD28 in RCC patients, and determined their relations with various clinicopathological characteristics. Elevated preoperative serum levels of PD-L1 and B7-H4 were correlated with less differentiated tumors, higher invasive and metastatic potential, a worse response to anti-VEGF therapy, and shorter overall survival. These findings suggested that investigating preoperative serum levels of PD-L1 and B7-H4 might not only be useful to assess the biological aggressiveness of RCCs, but also to predict the efficacy of anti-VEGF therapy and the eventual prognosis, indicating the future design of clinical trials of therapies targeting immune checkpoint in advanced RCCs.