ZNF148 (ZBP-89, Zfp148) is a multifunctional transcription factor expressed at low levels in most tissues. When overexpressed in gastrointestinal cancer cell lines, ZNF148 inhibits cellular proliferation and induces apoptosis. We sought to determine whether intestinal ZNF148 overexpression would abrogate adenoma development in the Apc^Min/+ mouse, i.e., whether ZNF148 is a tumor suppressor. The 13-kb villin promoter was spliced upstream of the ZNF148 cDNA to generate transgenic villin-ZNF148 (ZNF148^TgVZ) mice. Intestinal mucosal ZNF148 expression was elevated in four of five ZNF148^TgVZ lineages and correlated with increased caspase-3 expression and activation. In addition, DNA fragmentation was increased in ZNF148^TgVZ mice relative to wild-type littermates. These results suggested that increased intestinal ZNF148 expression induces apoptosis. ZNF148^TgVZ mice were crossed with Apc^Min/+ mice to assess the biological significance of intestinal ZNF148 overexpression. The presence of the ZNF148^TgVZ allele in Apc^Min/+ mice correlated with reduced gastrointestinal bleeding at 5 weeks, a 50% reduction in adenoma burden at 20–22 weeks, and prolonged survival (median survival of 33.5 days vs. 21.5 days), relative to nontransgenic littermates. These data suggest that enhanced ZNF148 expression activates intestinal apoptosis and thereby mitigates disease burden in Apc^Min/+ mice. They also suggest that ZNF148 is a therapeutic target to inhibit colon cancer development.