The role of the nuclear peroxisome proliferator-activated receptor-γ (PPAR-γ) in colon tumorigenesis remains controversial. Notwithstanding evidence that PPAR-γ ligands impede murine colorectal carcinogenesis, PPAR-γ agonists have been shown to enhance in vivo tumor formation in mouse models of human colon cancer. Our study was designed to determine whether troglitazone (TGZ) induces colonic tumor formation in normal C57BL/6J mice and enhances colorectal carcinogenesis in double mutant Apc1638N/+Mlh1+/− mice fed a standard AIN-76A diet. We report herein that not only does TGZ enhance carcinogenesis in the large intestine of mutant mice predisposed to intestinal carcinogenesis but TGZ also induces colonic tumors in normal mice without gene targeting or carcinogen administration. This observation indicates that preexisting mutational events are not necessary for induction of colonic tumors by activated PPAR-γ in vivo. © 2005 Wiley-Liss, Inc.