Our objective was to determine how dexamethasone (Dex) affects gastrointestinal protein metabolism and growth in neonatal pigs. Two-day-old pigs were given daily subcutaneous injections of either Dex (1 mg/kg body wt, n = 7) or saline (control, n = 6) for 7 days. In vivo protein synthesis was measured after 7 days with a bolus of [3H]phenylalanine. Tissue protein contents were measured in an initial control group of 2-day-old pigs and in control and Dex pigs after 7 days to estimate protein accretion and degradation. In control pigs, the protein accretion in the ileum was nearly sixfold greater than in the jejunum during the 7-day period. Dex nominally altered stomach growth but completely blocked the accretion of protein and DNA in the jejunum and ileum, with reduced villus height in the ileum. Dex increased the fractional protein degradation rate in the ileum (28%) and decreased the absolute protein synthesis rate in the jejunum and ileum by 17 and 21%, respectively. Dex resulted in a 40% lower total intestinal lactase activity compared with controls via reductions in both specific activity and tissue mass, especially in the ileum. Dex significantly decreased the circulating concentrations of insulin-like growth factor (IGF) I and IGF-binding protein (IGFBP)-1, -2, and -3. However, the tissue abundance of the IGF-I receptor in the stomach and ileum was greater in Dex pigs than controls. Our results suggest that Dex significantly inhibits small intestinal growth via both increased degradation and decreased synthesis of protein. Furthermore, the inhibition of intestinal growth resulted in significantly decreased lactose digestive capacity.