Down-regulation of XIAP (X-linked inhibitor of apoptosis protein) sensitizes colon cancer cells to the anticancer effect of peroxisome proliferator-activated receptor- (PPAR) ligands in mice. The aims of this study were to evaluate the effect of embelin (2,5-dihydroxy-3-undecyl-1,4-benzoquinone), an antagonist of XIAP, on colon cancer, with a particular focus on whether PPAR is required for embelin to exert its effect. A dominant-negative PPAR was used to antagonize endogenous PPAR in HCT116 cells. Cells were treated with or without embelin. Cell proliferation, apoptosis, and nuclear factor-B (NF-B) activity were measured. For in vivo studies, 1,2-dimethylhydrazine dihydrochloride (DMH) was s.c. injected to induce colon cancer in PPAR^+/+ and PPAR^+/– mice. Mice were fed embelin daily for 10 days before DMH injection, and continued for 30 more weeks. Embelin inhibited proliferation and induced apoptosis in HCT116 cells with marked up-regulation of PPAR. In addition, embelin significantly inhibited the expressions of survivin, cyclin D1, and c-Myc. These effects were partially dependent on PPAR. PPAR^+/– mice were more susceptible to DMH-induced colon carcinogenesis than PPAR^+/+ mice, and embelin significantly reduced the incidence of colon cancer in PPAR^+/+ mice but not in PPAR^+/– mice. Embelin inhibited NF-B activity in PPAR^+/+ mice but marginally so in PPAR^+/– mice. Thus, reduced expression of PPAR significantly sensitizes colonic tissues to the carcinogenic effect of DMH. Embelin inhibits chemical carcinogen-induced colon carcinogenesis, but this effect is partially dependent on the presence of functional PPAR, indicating that PPAR is a necessary signaling pathway involved in the antitumor activity of normal organisms. [Cancer Res 2009;69(11):4776–83]