Background: Single nucleotide polymorphisms (SNP) in critical signaling pathways may impact the outcome of metastatic renal cell cancer (mRCC) patients (pts) treated with VEGF targeted agents. Methods: Germline DNA was extracted from 263 pts of European-American ancestry enrolled in a prospective protocol with full baseline and follow up clinical data. A total of 113 common SNPs within select genes involved in RCC pathogenesis, angiogenesis and drugs metabolism were genotyped and associations sought with clinical outcome. The primary endpoint was progression free survival (PFS), defined as time from VEGF targeted therapy to progression or death. Cox model tested for the association between SNPs with PFS in univariate and multivariate model that adjusted for age, gender, type of VEGF inhibitor and MSKCC risk score. The false discovery rate (pFDR) was used to control for the number of tests performed. Results: The median follow-up time was 51.6 months (mo), 81% of pts had progression or death events. All patients were treated with an approved VEGF targeted agent (bevacizumab, sunitinib, sorafenib or pazopanib). Fifty three percent (140/263) of pts were treated with sunitinib. Two SNPs, one in HIF2α and one in VEGFR2, showed a significant association with the risk of progression. Compared to the dominant genotype (frequency 83%, median PFS 10.1mo), the VEGFR2 rs2305948 variant genotype (frequency 17%) showed a superior PFS (median 19.2mo) corresponded to an adjusted hazard ratio (HR) of 0.56 (95%CI: 0.37-0.84; p=0.005). Similarly and compared to the dominant genotype (frequency 94%, median PFS 10.6mo), the HIF2α rs11687512 variant genotype (frequency 6%) had a superior PFS (median 26.5mo) with an adjusted HR of 0.33 (95%CI 0.16-0.68; p=0.002). The analysis adjusted for age, gender, type of VEGF targeted therapy (Sunitinib vs. others) and MSKCC risk score. False discovery rate was <20% with both SNPs. Conclusions: Inherited variants may influence the PFS of pts with mRCC treated with VEGF targeted agents. Validation of these findings in an independent cohort is required. If validated, these results could help identifying subset of pts that are more likely to remain progression free on treatment.