Abstract Mutation of the genes encoding the WNT signaling components adenomatous polyposis coli or β-catenin plays a critical role in the initiation of colorectal cancer. These mutations cause constitutively active β-catenin/TCF–mediated transcription, driving the transformation of intestinal crypts to colorectal cancer precursor lesions, called dysplastic aberrant crypt foci. CD44 is a prominent WNT signaling target in the intestine and is selectively expressed on the renewing epithelial cells lining the crypts. The expression of CD44 is dramatically increased in aberrant crypt foci in both humans and tumor-susceptible ApcMin/+ mice, suggesting a role for CD44 in intestinal tumorigenesis. To study this role, we crossed C57BL/6J-Cd44−/− mice with C57BL/6J-ApcMin/+ mice. Compared with C57BL/6J-Cd44+/+/ApcMin/+ mice, C57BL/6J-Cd44−/−/ApcMin/+ mice showed an almost 50% reduction in the number of intestinal adenomas. This reduction was primarily caused by a decrease in the formation of aberrant crypts, implying the involvement of CD44 in tumor initiation. The absence of CD44 in the normal (nonneoplastic) crypts of Cd44−/−/ApcMin/+ mice did not alter the proliferative capacity and size of the intestinal stem cell and transit-amplifying compartments. However, compared with Cd44+/+/ApcMin/+ mice, Cd44−/−/ApcMin/+ showed an increase in the number of apoptotic epithelial cells at the base of the crypt which correlated with an increased expression of the proapoptotic genes Bok and Dr6. Our results show an important role for CD44 in intestinal tumorigenesis and suggest that CD44 does not affect proliferation but is involved in the control of the balance between survival and apoptosis in the intestinal crypt. [Cancer Res 2008;68(10):3655–61]