The overall goal of this research was to separate out the effects of butyrate from its fiber source and determine in vivo if it upregulates colonic histone acetylation, p21(Waf1/Cip1) expression (p21) and apoptosis and if this sequela of events is protective against aberrant crypt foci (ACF) formation. Eighty Sprague-Dawley rats were provided defined diets with either corn oil or fish oil as the lipid source, +/- butyrate-containing capsules targeted for release in the colon and +/- azoxymethane (AOM) (10 rats per group). Diets were provided for 11 weeks and at termination colonocyte nuclear histone H4 and p21 expression were determined by immunohistochemistry, apoptosis was measured by the terminal deoxynucleotide transferase biotin-dUTP nick end labeling assay and aberrant crypt numbers and multiplicity were enumerated. Luminal butyrate levels were also quantified. AOM injection repressed p21 expression, which was reversed by butyrate supplementation. Although butyrate enhanced p21 expression with both dietary lipid sources, the increase in p21 resulted in an increase in apoptosis and decrease in ACF with fish oil, but had no effect on apoptosis and increased ACF with corn oil. This significant interaction between fat, butyrate (fiber) and p21 expression with one combination being protective and the other promotive of colon carcinogenesis reinforces the importance of considering diet as a key factor in chemoprevention.