Background: Sunitinib is approved as systemic therapy for mRCC, GIST and pNET. Interpatient variability in the pharmacokinetics (PK) of sunitinib is high, which may have serious consequences for efficacy and toxicity of the drug. The objective of this study was to evaluate whether polymorphisms in candidate genes involved in sunitinib metabolism are related to the PK of sunitinib and its active metabolite SU12662. Methods: In this multicenter study, steady state sunitinib plasma concentrations and genotypes were prospectively obtained from 115 patients. Single nucleotide polymorphisms (SNPs) and haplotypes in 8 genes encoding CYP1A1, CYP3A4, CYP3A5, ABCB1, ABCG2, NR1I2, NR1I3, and PORwere evaluated as covariates in a population pharmacokinetic model describing both sunitinib and SU12662 PK using NONMEM. First, candidate genotypes/haplotypes were individually tested for a potential association with sunitinib or SU12662 clearance. Next, potential significant SNPs (p<0.05) were simultaneously included in a multivariate model and tested by backward elimination with a significance threshold of p<0.0005. Results: Four out of 37 screened genotypes (from 14 different SNPs) were related to sunitinib clearance (CYP3A4*22 CC and CT, CYP3A5*3 GG, and ABCB1 (2677 TT)). CYP3A5*3 AG genotype was associated with clearance of SU12662. In the multivariate analysis, none of the SNPs reached the predefined significance threshold of p<0.0005. Nevertheless, CYP3A4*22T allele carriers showed a 22.5% decreased clearance of sunitinib (p<0.01). Conclusions: Our data suggest that individual SNPs or haplotypes in CYP1A1, CYP3A4, CYP3A5, ABCB1, ABCG2, NR1I2, NR1I3 and POR are not clearly associated with sunitinib or SU12662 clearance. Several (environmental) factors may also influence the PK of sunitinib. Interestingly, the recently identified CYP3A4*22 SNP potentially has an impact on drug exposure. Replication studies in larger groups of patients are needed to verify the role of CYP3A4*22 for sunitinib clearance.