Intestinal mucin gene MUC2 is abundantly expressed in goblet cells. To identify the transcriptional activator that regulates goblet-specific expression of MUC2, we analyzed the interaction between the MUC2 promoter and homeodomain proteins CDX1/2, which are involved in the regulation of intestinal development and differentiation. COS-7 cells were transiently transfected with a CDX1 or CDX2 expression construct and then used for the luciferase assay, reverse transcription-polymerase chain reaction, and electrophoretic mobility shift assay (EMSA). The CDX2 expression construct activated the MUC2 promoter and increased the endogenous MUC2 mRNA level, while the CDX1 one did not. EMSA revealed that CDX2 bound to the MUC2 gene cis element, MUC2-WT. These results suggest that CDX2, but not CDX1, interacts with the MUC2 promoter and activates MUC2 transcription, and plays an important role in the differentiation of goblet cells.