AbstractWe examined the effect of dietary fat and colon tumorigenesis on the morphology and function of the rat mesenteric lymph node (MLN) and spleen at two stages of tumor development. Male Sprague‐Dawley rats were fed semipurified diets of varying fat content (5% mixed fat, 24% beef fat, 24% corn oil, or 24% Crisco) and treated for five weeks with either the colon carcinogen 1,2‐dimethylhydrazine (DMH) or the vehicle (saline). Animals consuming high‐fat diets had an increased incidence of splenic follicular and germinal center hyperplasia. Carcinogen treatment had no significant effect on the histological morphology of the spleen. MLN morphology was not dramatically affected by either diet or DMH treatment. At this time period, the splenic lymphocyte transformation response induced by concanavalin A (Con A), phytohemagglutinin, or pokeweed mitogen was significantly depressed in the group fed 24% corn oil (vehicle‐treated) and in the DMH‐treated groups fed 5 %fat compared with the vehicle‐treated group fed 5% fat. In contrast, the MLN transformation response was elevated in the group fed 24% Crisco. DMH treatment did not significantly influence the MLN response. Four months after carcinogen or vehicle treatment, at the point of colon tumor development, no statistically significant differences were seen in the splenic or MLN blastogenic responses of DMH‐or saline‐treated animals. Splenic natural killer cell cytotoxic activity wasalso not significantly affected by dietary fat, carcinogen treatment, or tumor development.