Recent epidemiologic studies have implicated red meat consumption as a risk factor for colon cancer in both men and women. However, it has been very difficult to separate the effects of meat as a protein source from the accompanying fat content of the diets analyzed in these studies. Experimental data from rodent feeding trials show mixed results, with no firm conclusions being possible in terms of the colon-cancer promoting effects of meat fat. The goal of the present study was to compare, in an experimental animal model, the effects of beef with casein as a protein source, within the context of a low- and high-fat diet containing either corn oil or beef tallow, on promotion of colon carcinogenesis. Tumors were induced in Sprague- Dawley rats with 1,2-dimethylhydrazine (20 mg/kg body wt for 10 weeks). Two hundred and eighty male weanling rats were randomized to eight dietary treatment groups of a 2×2×2 factorial design with fat source (corn oil vs. beef tallow), fat level (5% vs. 20%), and protein source (very lean beef vs. casein) as the factors. Diets were fed ad libitum before, during and after carcinogen treatment for a total of 27 weeks. At termination of the study, animals were examined for location, size and type of colon or extracolonic lesions. The total incidence and number of colon tumors were significantly lower in the groups fed beef rather than casein. High fat levels, regardless of source, significantly increased the number of colon adenomas. These results demonstrate that when lean beef is used as the protein source in the context of a low-fat diet, fewer intestinal tumors develop. These data do not support the belief that red meat consumption increases the risk for colon cardnogenesis, but underscores the importance of fat level in dietary context.