Elimination of both alleles of the gene that encodes the cyclin kinase inhibitor p21(WAF1/cip1) increases the frequency and size of intestinal tumors in Apc1638+/- mice that inherit a mutant allele of the Apc gene, and intermediate effects are seen if a single p21 allele is inactivated. The increased tumor formation is associated with altered cell maturation in the intestinal mucosa of the p21-deficient mice--increased cell proliferation, and decreased apoptosis, and goblet cell differentiation--that is also a function of p21 gene dosage. Moreover, a Western-style diet that mimics principal risk factors for colon cancer (high fat and phosphate, low calcium and vitamin D) accelerates tumor formation in Apc1638+/- mice, and the loss of a single or both p21 alleles is additive with the tumor-promoting effects of this diet, resulting in more and larger tumors, and a highly significant decrease in survival time. Thus, p21 normally suppresses Apc-initiated tumor formation and is haplo-insufficient in this regard. This is consistent with recent reports that Apc initiates tumor formation by up-regulating c-myc expression through altered beta-catenin-Tcf signaling and that c-myc then up-regulates cdk4, whose activity is inhibited by p21. Decreased expression of p21 is also a marker of poor prognosis in patients, and the data presented suggest that dietary alterations in patients undergoing treatment for colon cancer might be highly effective in improving outcome.