AbstractThe effect of two levels and types of dietary fats on the susceptibility of colonic cells to the nuclear‐damaging effect of 1,2‐dimethylhydrazine dihydrochloride (DMH), 2‐amino‐3, 4‐dimethylimidazo(4,5‐f)quinoline (MelQ), and gamma‐radiation was investigated. Corn oil and beef tallow were added to the semisynthetic diet at 5% and 20% levels (weight/weight). A diet‐related effect was not evident until after two weeks of feeding. Animals (C57BL/6J female mice) that were given the 20% corn oil or beef tallow diets had significantly (p<0.05) more nuclear aberrations in their colons 24 hours following treatment with DMH (5 mg or 10 mg/kg body wt or MelQ (100 mg/kg body weight) than did those given low‐fat diets (5% corn oil or beef tallow). The nuclear‐damaging effect of gamma radiation was unaffected by dietary treatments. A high‐fat diet had the most pronounced effect on DMH‐treated animals, and maximum nuclear aberrations were observed 24 hours following the treatment. Thus, we concluded that increased levels of dietary fats elevate the toxicity of DMH and MelQ to colonic epithelial cells.