Corn oil administered by oral gavage decreases the spontaneous incidence of mononuclear cell leukemia (MNCL) in male Fischer rats used as vehicle controls in long-term carcinogenesis experiments. We used an MNCL transplant model, an in situ MNCL cell proliferation assay and immune competence assays to explore mechanism(s) underlying the effects of corn oil gavage on MNCL development in male rats. Relative to non-gavaged or water-gavaged rats, corn oil-gavaged rats had approximately 25% lower MNCL incidence as well as longer MNCL latency and increased survival. There were no differences in body weight or caloric intake between treatment groups, as corn oil-gavaged rats compensated for calories supplied by the gavaged oil by consuming less food. These data indicate that transplanted MNCL cells grew slower in corn oil-gavaged rats than in non-gavaged or water-gavaged rats and suggest that corn oil gavage may exert its effects through a decrease in protein or other nutrients. Five-day proliferation rates of cultured MNCL cells in diffusion chambers implanted in male corn oil-gavaged rats were 40% less than in water-gavaged rats, suggesting nutrition-sensitive endogenous factors mediate the suppression of MNCL cell proliferation in corn oil-gavaged rats. Corn oil-gavaged rats had 54% lower serum growth hormone (GH) levels, and replacement of GH into corn oil-gavaged rats by osmotic minipump infusion increased in situ MNCL cell proliferation to rates observed in water-gavaged animals. Corn oil-gavaged rats also showed enhanced cellular immune competence as measured by mitogen stimulation, natural cytotoxicity and immunofluorescence assays. Taken together, these findings suggest corn oil administered by oral gavage may decrease MNCL development by slowing MNCL cell proliferation, mediated at least in part by altered levels of diffusible factors such as GH, and/or by enhancing immune competence.