Background: Sunitinib is a tyrosin kinase inhibitor with proven efficacy in renal clear cell carcinoma (RCCC). However properly validated molecular predictors of response or toxicity are still lacking. This study aims to identify such genetic markers focusing on the pharmacokinetics and pharmacodynamics pathways of the drug. Methods: An observational prospective study involving 15 centers of the Spanish Oncology Genitourinary Group (SOGUG) was designed to collect DNA from RCCC sunitinib-treated patients. Eligibility criteria included patients with locally, advanced or metastatic clear renal cell carcinoma treated with sunitinib in a daily practice setting and no prior systemic treatment (neither chemotherapy nor immunotherapy). A total of 15 key polymorphisms in 8 genes involved in the pharmacokinetics (CYP3A4, CYP3A5, ABCB1 and ABCG2) and pharmacodynamics (VEGF, VEGFR2, VEGFR3 and PDGFRa) of the drug were selected to perform a genotype-phenotype analysis. Results: From February 2008 trough December 2010, 100 patients have been included. Regarding clinical factors prognostic classification of the MSKC showed a significant correlation with TTP (p=0.014). Among the polymorphisms studied, two VEGFR3 SNPs presented statistically significant associations with sunitinib TTP (HR=4.3, 95%CI= 2.1-8.8, P=6x10^-5 and HR=3.6, 95%CI=1.9-6.8, P=10^-4, per allele in multivariate analysis), clinical benefit (HR=12.4, 95%CI= 2.0-77, P=0.007 and HR=5.9, 95%CI= 1.3-28, P=0.024, per allele in multivariate analysis) and one of them with OS (HR=7.5, 95%CI= 1.6-35, P=0.01) favouring wild type patients. Two ABCB1 SNPs also showed a significant association with TTP. In relation to toxicities, one CYP3A5 SNP showed a trend towards an increased risk for grade 3/4 toxicity (P=0.052). Conclusions: To the best of our knowledge this is the first time a relevant role of VEGFR3 polymorphisms in response to first line treatment for renal clear cell carcinoma is found. If confirmed, inhibition of this target could have therapeutic implications.