Molecular markers of sorafenib efficacy in patients with metastatic renal cell carcinoma (mRCC) are not available. The purpose of this study was to discover genetic markers of survival in patients with mRCC treated with sorafenib. Germline variants from 56 genes were genotyped in 295 patients with mRCC. Variant-overall survival (OS) associations were tested in multivariate regression models. Mechanistic studies were conducted to validate clinical associations. rs1885657, ITGAV rs3816375, and WWOX rs8047917 (sorafenib arm), and rs307826 and VEGFA rs3024987 (sorafenib and placebo arms combined) were associated with shorter OS. rs307826 increased VEGFR-3 phosphorylation, membrane trafficking, and receptor activation. VEGFA rs1885657 and rs58159269 increased transcriptional activity of the constructs containing these variants in endothelial and RCC cell lines, and rs58159269 increased endothelial cell proliferation and tube formation. rs307826 and rs58159269 led to reduced sorafenib cytotoxicity. Genetic variation in and could affect survival in sorafenib-treated patients with mRCC. These markers should be examined in additional malignancies treated with sorafenib and in other angiogenesis inhibitors used in mRCC. SIGNIFICANCE: Clinical and mechanistic data identify germline genetic variants in and as markers of survival in patients with metastatic renal cell carcinoma.