Earlier studies have shown that the uptake of intact proteins from the intestinal lumen into the systemic circulation is increased in neonates. The present experiments tested the uptake of trypsin in newborn compared with 4-wk-old weaned rabbits. Trypsin (200 mg/100 g body wt) was administered by gavage to newborn and 4-wk-old rabbits. Four hours later, the tryptic activity and immunoreactive trypsin (i-trypsin) content of serum from newborn rabbits exceeded that of the older animals. After Sephadex G-200 gel filtration of serum from animals gavaged with trypsin, tryptic activity was detected in the excluded volume (presumably reflecting trypsin bound to alpha 2-macroglobulin), and i-trypsin was detected in the included volume (presumably reflecting trypsin bound to alpha 1-antitrypsin). In vitro experiments demonstrated that large amounts of trypsin were required to overwhelm the antiprotease present in normal rabbit serum. We suggest that complete or partial deficiencies of serum protease inhibitors may permit proteases taken up from the intestinal lumen of the neonate to circulate, reach the liver, and induce tissue injury at this site.