Background: Diarrhea, HFS, and hypertension are common toxicities of sorafenib. No markers are validated to predict patients at risk of these toxicities. This study aimed to identify genetic predictors of sorafenib-induced toxicities. Methods: A two-step, discovery-validation approach was used. The discovery set included 140 renal cell carcinoma patients from the TARGET study treated with sorafenib (400 mg twice daily) and genotyped for 1040 single-nucleotide polymorphisms (SNPs) in 56 genes. The three most statistically significant SNPs associated with grade ≥2 composite toxicity (either hypertension, diarrhea, HFS, or other skin toxicities, CTCAE v.3.0) were tested for association with grade 3 composite toxicity (either hypertension, diarrhea, or HFS, CTCAE v.4.0) in a validation set of 240 hepatocellular carcinoma patients from Alliance/CALGB 80802 treated with sorafenib (400 mg twice daily) alone or with doxorubicin. Associations between SNPs and composite toxicity was performed by logistic regression, with adjusting covariates (age, gender, race, and treatment arm, the latter two covariates for the validation set only). A meta-analysis odds ratio (OR) of each SNP-grade 3 toxicity association between the discovery and validation sets was obtained by inverse variance to point toward effects specific to a type of toxicity. Results: In the discovery set, the top three SNPs associated with grade ≥2 composite toxicity were rs12366035 (C>T, minor allele frequency, MAF 0.34) in VEGFB (p 0.0007), rs4035887 (G>A, MAF 0.49) in EPAS1 (p 0.0021), and rs4864950 (T>A, MAF 0.23) in KDR (p 0.0058). These SNPs were genotyped in the validation set and only rs4864950 in KDR was replicated. No grade 4 toxicities were reported. Similar to the discovery set (OR 2.41, 95% CI 1.29-4.51), the A allele of rs4864950 increased the risk of grade 3 composite toxicity (p 0.032, OR 2.12, 95% CI 1.70-4.27) in the validation set. Grade 3 toxicity prevalence in the discovery and validation sets were 3.6% and 7.4% diarrhea, 8.6% and 12.3% HFS, 3.6% and 8.8% hypertension, respectively. The meta-analysis of the two datasets showed that the A allele of rs4864950 increased the risk of grade 3 diarrhea (p 0.045, OR 3.09, 95% CI 1.03-9.29), grade 3 HFS (p 0.012, OR 2.57, 95% CI 1.24-5.37), but not grade 3 hypertension (p 0.207, OR 0.51, 95% CI 0.18-1.45). Conclusions: We provide the first evidence of clinical validity of a marker of sorafenib-induced diarrhea and HFS. Sorafenib inhibits VEGFR2 (coded by KDR), leading to epithelial hypoxia and causing diarrhea and HFS. Variant rs4864950 might affect the function VEGFR2, which, during VEGFR2 inhibition, increases the risk of diarrhea and HFS. This SNP is common and can be genotyped in patients before receiving sorafenib for a better risk assessment. Support: U10CA180821, U10CA180882, U24CA196171; https://acknowledgments.alliancefound.org ClinicalTrials.gov Id: NCT01015833.