Background: Alterations in DNA damage repair (DDR) genes are associated with human tumorigenesis and may be as potential biomarkers for vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) therapy in renal cell carcinoma. However, biologic significance and relevance to TKI targeted therapy in metastatic RCC are unknown. Methods: Genomic data and treatment outcomes were retrospectively collected for patients with metastatic RCC. Tumor and germline DNA were subject to targeted next generation sequencing across 642 genes of interest, including 60 DDR genes. Patients were dichotomized according to underlying DDR gene alteration into (1) DDR gene alterations present (Mut DDR); (2) wildtype (WT) DDR gene alterations present (WT DDR). Association between DDR status and therapeutic benefit was investigated separately for and vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) therapy. Results: Mut DDR were detected in 17/40 patients (42.5%). The most frequently DDR altered genes were TP53. For patients with TKI treatment, Mut DDR status was associated with superior progression free survival (log-rank p = 0.048), but not with superior overall survival (log-rank p = 0.39); after adjusting for International Metastatic Renal Cell Carcinoma Database Consortium risks and extent of prior therapy, the HR for Mut DDR was 2.68 (95% CI: 0.96–7.46; p = 0.059). Conclusions: DDR alterations are recurrent genomic events in patients with advanced RCC and were mostly clonal in this cohort. Dysfunction events in these genes may affect outcome with TKI therapy in adanced RCC, and these hypothesis-generating results deserve further study.