Background: Renal cell carcinoma (RCC) comprises a heterogeneous group of tumors of different histological subtypes. Each subtype is characterized by distinct immunohistochemical and molecular features and different biology. Currently, patients with advanced RCC have poor disease outcomes despite recent breakthroughs in immunotherapy. Chimeric antigen receptor (CAR)-T cell therapy has produced remarkably effective and durable clinical responses in hematological malignancies. However, there have been very limited success of CAR-T cell therapy in solid tumors. CD70 and its signaling partner CD27 are cell surface molecules that have emerged as novel targets for immune modulation approach. CD70 is also a promising target for CAR-T cell therapy, as it is overexpressed on multiple types of solid tumors including RCC and not expressed in most normal tissue. Studies have shown clear cell RCC (CCRCC) commonly expresses CD70. To date, no studies has evaluated CD70 expression in metastatic RCC in comparison with primary RCC. Methods: Four Tissue Microarrays (TMAs) were constructed using 395 tumors from 374 patients with RCC, 4 to 8 cores per tumor. There were 359 primary tumors, 36 metastatic tumors, and 344 matched normal. The primary RCC included 309 CCRCC including 11 with sarcomatoid differentiation, 38 papillary RCC (pRCC) including 1 with sarcomatoid differentiation, 8 chromophobe RCC (ChRCC), and 4 collecting duct RCC (CDC). The metastatic RCC were composed of 31 CCRCC including 3 with sarcomatoid differentiation and 5 PRCC. CD70 expression was evaluated using immunohistochemistry (IHC) and Definiens image analysis. CD70 expression was measured using the percentage of CD70-positive tumor cells. A CD70-positive tumor was defined as CD70 immunopercentage ≥ cutoff value in at least one core. Results: CD70 staining was detected in tumor cells in primary and metastatic RCC, with minimal staining in normal renal parenchyma. When the positive cutoff was defined as ≥1% of tumor cells demonstrating CD70 staining, the positive rate in CCRCC, pRCC, ChRCC, CDC, and SarRCC was 98%, 32%, 0%, 11%, and 46%, respectively. When the positive cutoff was defined as ≥ 25% of tumor cells stained positive for CD70, the positive rate in CCRCC, pRCC, ChRCC, CDC, and SarRCC was 41%, 10%, 0%, 0%, and 23%, respectively. Finally, when the positive cutoff was defined as ≥50%, the positive rate in CCRCC, pRCC, ChRCC, CDC, and SarRCC was 22%, 2%, 0%, 0%, and 8%, respectively. Metastatic RCC showed a higher % of tumor cells expressing CD70 compared to primary RCC for patients with CCRCC (mean 15% vs 9%) or SarRCC (12% vs 9%). Conclusions: Clear cell and sarcomatoid RCC are the RCC subtypes that demonstrate the highest CD70 expression. CD70 expression is further increased in metastatic lesions compared to the primary tumors. Anti-CD70 CAR-T cell therapy may benefit a significant fraction of patients with advanced CCRCC and sarcomatoid RCC.