Allelic imbalance (AI) is a powerful tool to identify cis-regulatory variation for gene expression. UGT2B15 is an important enzyme involved in the metabolism of multiple endobiotics and xenobiotics. In this study, we measured the relative expression of two alleles at this gene by using SNP rs1902023:G>T. An excess of the G over the T allele was consistently observed in liver (P<0.001), but not in breast (P=0.06) samples, suggesting that SNPs in strong linkage disequilibrium with G253T regulate UGT2B15 expression in liver. Seven such SNPs were identified by resequencing the promoter and exon 1, which define two distinct haplotypes. Reporter gene assays confirmed that one haplotype displayed approximately 20% higher promoter activity compared to the other major haplotype in liver HepG2 (P<0.001), but not in breast MCF-7 (P=0.540) cells. Reporter gene assays with additional constructs pointed to rs34010522:G>T and rs35513228:C>T as the cis-regulatory variants; both SNPs were also evaluated in LNCaP and Caco-2 cells. By ChIP, we showed that the transcription factor Nrf2 binds to the region spanning rs34010522:G>T in all four cell lines. Our results provide a good example for how AI can be used to identify cis-regulatory variation and gain insights into the tissue specific regulation of gene expression.