Anticancer drugs have been reported to damage the intestinal mucosa. We evaluated the effects of caloric intake on the mucosal morphology and immune cells in rats treated with 5-fluorouracil (5-FU). Rats were received a liquid diet plus 5-FU treatment for 8 days as follows: Low calorie group (25 kcal/day with 5-FU), Normal calorie group (50 kcal/day with 5-FU), and Control group (50 kcal/day with saline). The mucosal morphology, cell numbers and phenotypes of spleen and intraepithelial lymphocytes (IEL) were assessed. As compared with the control group, the villus heights were significantly lower in the Low calorie group, but not significantly lower in the Normal calorie group. The total cell yield from the spleen, CD4+ and CD8+ T cells decreased in the Low and Normal calorie group, but these changes were less pronounced in Normal calorie group. The total cell yield from the IEL also decreased in the Low calorie group, but not in the Normal calorie group. Our study demonstrated that sufficient caloric intake attenuated the damages in intestinal morphology and in the immune cell numbers. Clinically, nutritional support would be expected to be one approach to reducing the risk of bacterial translocation or infection induced by chemotherapy.