The compromised human newborn frequently presents with overwhelming feeding problems which lead to inadequate intake. These problems may affect the development of the small intestine, especially mucosal barrier function, leading to increased infections and susceptibility to allergens. To study this, an animal model was established using neonatal rabbits deprived of nutrients from birth until 72 h. Mucosal barrier function was compared in deprived and control (naturally fed 72-h-old animals) rabbits by measuring immunoreactive bovine serum albumin in serum 4 h after intragastric infusion of crystalline bovine serum albumin (200 mg/100 g body weight). Trypsin activity was measured in rinse fluid obtained from the small intestine. Representative sections of jejunum from control and experimental animals were formalin fixed and stained with hematoxylin and eosin for morphologic comparison. Following the bovine serum albumin feeding, a significantly increased serum immunoreactive bovine serum albumin and significantly decreased trypsin-like activity of the small intestinal rinse fluid was noted in starved animals compared to controls. In addition, the enterocytes of malnourished animals were more cuboidal and contained fewer and smaller supranuclear granules on microscopic examination than the enterocytes of controls. This study suggests that short-term starvation in newborns affects mucosal barrier function. Acute starvation may place newborns at increased risk for infections and allergic disease.