Mammalian cells utilize two transporters for the uptake of ascorbic acid (AA), the sodium-dependent vitamin C transporter-1 & -2 (SVCT-1 and SVCT-2). In the intestine, these transporters are involved in the absorption of AA and are expressed at the apical and basolateral membrane domains of the polarized epithelia, respectively. Little is known about the differential expression of these two transporters along the anterior-posterior axis of the intestinal tract and the molecular mechanism(s) that dictate this pattern of expression. We addressed these issues using mouse and human intestinal cDNAs. The results showed a significantly lower rate of carrier-mediated AA uptake by mouse colon compared to jejunum. This was associated with a significantly lower level of expression of both the SVCT-1 and -2 at the protein, mRNA, and hnRNA levels in colon compared to jejunum, implying the involvement of transcriptional mechanism(s). Similarly, expression of SVCT-1 and -2 mRNA and hnRNA were found to be significantly lower in human colon. We also examined the levels of expression of HNF1α and Sp1 that drive the transcription of the Slc23a1 and Slc23a2 promoters, respectively, and found them to be markedly lower in the colon. Furthermore, significantly lower levels of the activating markers for histone modifications (H3K4me3 and H3K9ac) were observed in the Slc23a1 and Slc23a2 promoters in the colon. These findings show, for the first time, that the SVCT-1 and -2 are differentially expressed along the intestinal tract, and this pattern of expression is, at least in part mediated, via transcriptional/epigenetic mechanisms.