Genetically modified mice have been used for colon cancer research, but findings from these models are confounded by expression of cancer in multiple organs. We sought to create a transgenic mouse with Cre recombinase (Cre) expression limited to the epithelial cells of the large intestine and used this model to study colon cancer driven by adenomatosis polyposis coli (APC) gene inactivation. A promoter/enhancer from the mouse carbonic anhydrase I gene was used to generate a Cre-expressing transgenic mouse (CAC). After characterizing transgene expression and distribution, CAC mice were crossed to APC(580S) mice to generate mice with APC inactivation at one (CAC;APC(580S/+)) or both alleles (CAC;APC(580S/580S)). Transgene expression was limited to the epithelial cells of the cecum and colon, extended from the crypt base to the luminal surface, and was expressed in approximately 15% of the crypts. No abnormal gross phenotype was seen in 3- or 6-week-old CAC;APC(580S/+) mice, but CAC;APC(580S/580S) mice had significant mucosal hyperplasia in the colon at 3 weeks, which developed into tumors by 6 weeks. By 10 weeks, 20% of CAC;APC(580S/+) mice developed adenomatous lesions in the distal colon (3.0 +/- 0.4 mm; 1.1 per mouse). Dextran sulfate sodium treatment increased the incidence and number of tumors, and this occurred predominantly in distal colon. Our new model has improved features for colon cancer research, that is, transgene expression is limited to the epithelium of the large bowel with normal cells found next to genetically modified cells.