Background: CUP is a heterogeneous clinicopathologic syndrome representing many types of occult clinically undetectable primary neoplasms. With the advent of MTP, the tissue of origin in CUP is frequently identified when used in concert with immunohistochemistry (IHC) and clinical features. Histopathology alone is usually not specific, and diagnostic IHC is often limited. Diagnosis of the RCC subset of CUP has important therapeutic potential given the availability of multiple approved biologic therapies, and the use of MTP may facilitate the correct diagnosis. Methods: 488 CUP patients (pts) seen between 2008 – 2012 had MTP (RT-PCR 92-gene assay, CancerTYPE ID, bioTheranostics, Inc.) of their archived tumor specimens. The clinicopathologic features were reviewed and, where feasible, subsequent additional IHC stains were obtained to support the MTP diagnosis. The response and survival to first-line RCC site-specific therapy were evaluated. Results: RCC was the MTP diagnosis in 22 pts (4.5%), including papillary in 8, clear cell in 7, and unknown subtype in 7. Histology included poorly differentiated carcinoma in 15 and adenocarcinoma in 7 (4 with papillary features, 1 with clear cell features). None had evidence of a primary renal lesion detectable by abdominal computed tomography, and the sites of metastasis most often included retroperitoneal nodes (63%), mediastinal nodes (31%), lung (22%), and bone (18%). Diagnostic RCC IHC stains were performed initially in only 3 tumors (14%), but RCC IHC stains (RCC, PAX 8, others) performed later supported the MTP diagnosis in 7 of 9 tumors where remaining tissue was available. 16 pts received first-line RCC targeted therapies (objective response rate was 18%, median survival of 13.4). Conclusions: RCC is a subset of CUP which can be diagnosed by MTP. RCC is usually not suspected in the absence of clear cell features, and occult RCC appears to commonly be the papillary subtype. RCC IHC may be diagnostic in some CUP tumors, but may be omitted in the initial pathologic evaluation. CUP-RCC pts are important to identify as they may benefit from standard RCC targeted therapies, and respond poorly to empiric chemotherapy.