Orally administered systemically active steroids enhance the digestive and absorptive functions of the intestine, but their effect on lipid uptake is unknown. The effect of the locally acting steroid budesonide on intestinal absorptive function also is unknown. Accordingly, this study was undertaken to assess the influence of 4 wk of treatment of weaning male rats with a daily oral gavage of budesonide (BUD), prednisone (PRED), or control vehicle on the jejunal and ileal uptake of fatty acids and cholesterol. BUD enhanced jejunal uptake of oleic acid and ileal uptake of linoleic acid. PRED increased jejunal uptake of cholesterol and ileal uptake of lauric, palmitic, linoleic, and linolenic acids. Higher doses of BUD (up to 1 mg/kg) given to adult rats for 2 wk further increased the uptake of some lipids. The changes in the uptake of lipids were not due to variations in the weight of the intestinal mucosa or in the animals' food intake. Ileal ornithine decarboxylase mRNA expression was increased with PRED, but there were no steroid-associated changes in the expression of the mRNA of the early response genes c-myc, c-jun, or c-fos or of proglucagon, the liver fatty acid-binding protein (FABP), the ileal lipid-binding protein, tumor necrosis factor alpha, interleukin 2 (IL-2), IL-6, or IL-10. In summary, treatment of weanling rats with BUD and PRED enhances the uptake of some lipids by a process that is independent of the effects of early response genes and genes encoding cytokines, proglucagon, and FABP.