Background: Sunitinib (SU) is an oral small-molecule, multi-targeted receptor tyrosine kinase inhibitor, which is approved as first-line treatment for metastatic renal cell carcinoma (RCC). In a previous study, using a commercially available DNA microarray genotyping system, we identified a group of single nucleotide polymorphisms (SNPs) associated with survival and toxicity in RCC patients, treated with SU. In this study, we validated our previous data using an independent series (García-Donas J, et al. Lancet Oncol 2011). Methods: 27 metastatic RCC treatment-naive patients, recruited prospectively from January 2010 to May 2011. All the patients received SU standard treatment. A total of 92 of single nucleotide polymorphisms (SNPs) in 34 genes involved in the pharmacokinetic and pharmacodynamic pathways of drugs, were analyzed using Drug inCode pharmacogenetic service. For validation we performed genotyping in 83 samples using the KASPar SNP genotyping system. Results: In patients with CYP1A2*1F and CYP2C19 *2 and *4 polymorphisms, no statistically significant associations were observed, among drug metabolizing genes and toxicity or survival. Catechol-O-methyltransferase(COMT) is involved in the inactivation of several substances suchs as cathecolamines and estrogens and Val(158)Met polymorphism which were associated with PFS and OS, it was observed in our initial study. Met/Met and Val/Met carriers had statistical significant difference in PFS and OS (p = 0.0001 and p = 0.0001, respectively) compared to Val/Val carriers. In the validation series, we were able to confirm the effect on PFS (p = 0.0102). Conclusions: Our preliminary analysis suggested that CYP1A2*1F and CYP2C19*2 and *4polymorphism may be associated with SU toxicity in RCC patients, but findings were not validated in an independent series. However, we could confirm an association between COMT VAl(158)Met polymorphisms and PFS. To our knowledge this is the first study to report COMT polymorphism to be associated with RCC survival.