SUMMARY: Keratin 18 (K18) expression is a defining characteristic of internal epithelial cells of mammals. Here, we used the K18 gene and an internal ribosome entry site (IRES) to express green fluorescent protein, human placental alkaline phosphatase, and a modified Cre recombinase in an epithelial specific pattern in transgenic mice. The K18-driven alkaline phosphatase was expressed in liver, kidney, uterine endometrium, and other internal epithelia. The enzymatic activity of the Cre recombinase-mutant estrogen receptor fusion protein was dependent on tamoxifen administration and resulted in a mosaic pattern in internal epithelia, including bladder, uterus, liver, and kidney. This conditional Cre activity in internal epithelial organs should be valuable for strategies utilizing Cre for activation of gene expression. This study demonstrates that the tissue-specific, position-independent transcriptional activity of the K18 gene is not compromised by the use of an IRES element for the expression of a second protein from a bicistronic mRNA.