Diagnostic assessment occasionally presents carcinoma of unknown primary site (CUP) with metastatic renalcell carcinoma (mRCC) histologic and immunohistochemical characteristics (CUP-mRCC). We reviewed our single-institution experience and searched the PubMed database, and identified 10 patients treated at our institution; 60% were poor risk patients. Objective response rate was 40%, progression-free survival was 2.5 months, and overall survival was 5.7 months; and the literature search identified 42 CUP-mRCC cases, for a total of 52 cases of CUP-mRCC. Vascular endothelial growth factoretargeted therapy is valid, feasible, and safe in CUP-mRCC, and these patients should thus be identified among CUP patients for specific renal-cell carcinoma therapy. Background: Carcinoma of unknown primary site (CUP) is a heterogenous group of metastatic cancer with no detectable primary tumor site. Diagnostic assessment occasionally presents CUP with metastatic renal-cell carcinoma (mRCC) histologic and immunohistochemical characteristics (CUP-mRCC). Efficacy and toxicity data for vascular endothelial growth factor inhibitor therapies in CUP-mRCC patients are few. Patients and Methods: We retrospectively reviewed consecutive patients with CUP-mRCC at a single institution between 2007 and 2018. Treatment outcomes were assessed from initiation of renal-cell carcinomaespecific therapy, including response rate, progression-free survival, and overall survival. Results: Ten patients with CUP-mRCC were identified. Median age was 64 years. Histologies were clear-cell (30%), papillary type II (20%), and unclassified renal-cell (50%) carcinoma. International Metastatic Renal Cell Carcinoma Database Consortium risk group were favorable, intermediate, and poor in 0, 40%, and 60%, respectively. One patient received empiric first-line chemotherapy. Targeted treatments were pazopanib (n ¼ 7), sunitinib (n ¼ 2), and sorafenib (n ¼ 1). Objective response rate was 40%, progression-free survival was 2.5 months (95% confidence interval, 1.2-3.8), and overall survival was 5.7 months (95% confidence interval, 0-24.0). Stratified for International Metastatic Renal Cell Carcinoma Database Consortium risk, overall survival in intermediate versus poor risk group were 18.6 months and 2.3 months, respectively. Second-line therapy did not result in disease control. No new or unexpected toxicities were observed. Conclusion: CUP-mRCC treated with vascular endothelial growth factoretargeted therapy is valid, feasible, and safe even though these patients had several negative prognostic factors. CUP-mRCC patients should be identified among CUP patients for specific renal-cell carcinoma therapy.