Previous studies have demonstrated that abdominal irradiation alters intestinal uptake of nutrients. The purpose of this study was to determine the effect of an orally administered synthetic prostaglandin E2, enprostil, given on three occasions shortly prior to a single exposure to 600 cGy external abdominal irradiation, on intestinal active and passive transport processes and villus morphology measured 7 days later. Animals were sham-irradiated (CONT) or were exposed to a single dose of 600 cGy external abdominal irradiation (RAD); two and one mornings before the day of irradiation or sham irradiation, and 1 h before irradiation or sham irradiation enprostil was administered. One half of CONT and RAD groups were dosed orally with enprostil, 5 μg/kg body weight, and the other half of the CONT and RAD groups were dosed with placebo. Seven days later the in vitro uptake of glucose, galactose, long-chain fatty acids, and cholesterol was determined in the four groups (CONT with and without enprostil, and RAD with and without enprostil). In CONT, enprostil was associated with increased jejunal uptake of glucose and ileal uptake of galactose. In RAD given enprostil, there was increased jejunal uptake of galactose but reduced ileal uptake of glucose and galactose. The expected radiation-associated decline in jejunal galactose uptake was prevented with enprostil. In CONT given enprostil, there was increased jejunal uptake of fatty acid (FA) 14:0 and 16:0 but reduced uptake of FA 18:0, 18:1, and 18:2; enprostil had no effect on lipid uptake in the ileum in CONT. Enprostil had a different effect in RAD, with reduced jejunal uptake of FA 14:0; 16:0, 18:0, 18:3, and cholesterol and reduced ileal uptake of FA 16:0, 18:1, 18:2, 18:3, and cholesterol. Enprostil was associated with a reduced jejunal mucosal surface area in CONT and a reduced ileal mucosal surface area in RAD. The irradiation-associated decline in body weight was not observed in animals given enprostil despite the lack of change in food intake. The alterations in nutrient uptake were not due to differences in food intake, weight change, or mucosal surface area. Thus, enprostil given on three occasions just before a single dose of abdominal irradiation was associated with increased intestinal uptake of galactose, but failed to prevent most of the other irradiation-associated changes in active and passive intestinal transport, and accentuated rather than prevented the irradiation-associated diminution in mucosal surface area.Key words: adaptation, cholesterol, fatty acids, galactose, glucose, ileum, jejunum.