BACKGROUND AND AIMS: The transcription factor signal transducer and activator of transcription 3 (Stat3) has been considered to promote progression and metastasis of intestinal cancers. METHODS: We investigated the role of Stat3 in intestinal tumors using mice with conditional ablation of Stat3 in intestinal epithelial cells (Stat3(DeltaIEC)). RESULTS: In the Apc(Min) mouse model of intestinal cancer, genetic ablation of Stat3 reduced the multiplicity of early adenomas. However, loss of Stat3 promoted tumor progression at later stages, leading to formation of invasive carcinomas, which significantly shortened the lifespan of Stat3(DeltaIEC)Apc(Min/+) mice. Interestingly, loss of Stat3 in tumors of Apc(Min/+) mice had no significant impact on cell survival and angiogenesis, but promoted cell proliferation. A genome-wide expression analysis of Stat3-deficient tumors suggested that Stat3 might negatively regulate intestinal cancer progression via the cell adhesion molecule CEACAM1. CONCLUSIONS: Our data suggest that Stat3 impairs invasiveness of intestinal tumors. Therefore, therapeutic targeting of the Stat3 signaling pathway in intestinal cancer should be evaluated for adverse effects on tumor progression.