Breast cancer resistance protein (BCRP), the second member of the ATP-binding cassette membrane transporter family, has a single nucleotide polymorphism, C421A (resulting in Q141K), that is of functional importance. Our aim was to explore the relationship between this polymorphism of the BCRP gene and the risk of renal cell carcinoma (RCC) development. For a case-control study, DNA samples from 200 nonpapillary RCC patients and 200 healthy control subjects were analyzed using the TaqMan technique. The genotypic frequencies of the BCRP C421A polymorphism were compared between RCC patients and control subjects. The frequency of the C/C genotype was significantly higher in RCC patients than in control subjects (age- and gender-adjusted OR = 1.96, 95% CI 1.32-2.93). No associations were observed between the BCRP C421A polymorphism and clinicopathologic or epidemiologic factors, including age, gender, tumor grade, stage, cigarette smoking, family history of cancer and body mass index. Carriers with the C/C genotype of the BCRP C421A polymorphism are at risk of developing nonpapillary RCC. These data suggest that BCRP is a candidate RCC susceptibility gene.