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Intestinal P-glycoprotein, which is encoded by the MDR1gene, plays an important role in the absorption and presystemic elimination of many xenobiotics. Hence, an understanding of the factors regulating its expression and function is of substantial interest. In addition to genetic factors, exposure to drugs such as rifampin can profoundly affect its expression. So far, the mechanisms by which rifampin induces MDR1expression are poorly understood. Recent studies demonstrate that the nuclear receptor PXR (pregnane X receptor) is involved in xenobiotic induction of CYP3A4. Because CYP3A4and MDR1are often co-induced, we investigated whether a similar mechanism is also involved in MDR1induction. The human colon carcinoma cell line LS174T was used as an intestinal model to study induction because in these cells the endogenous MDR1gene is highly inducible by rifampin. The 5′-upstream region of human MDR1was examined for the presence of potential PXR response elements. Several binding sites were identified that form a complex regulatory cluster at about −8 kilobase pairs. Only one DR4 motif within this cluster is necessary for induction by rifampin. We conclude that induction of MDR1is mediated by a DR4 motif in the upstream enhancer at about −8 kilobase pairs, to which PXR binds.