Secretory leukocyte protease inhibitor (SLPI) is the dominant protease inhibitor in the mucus secretions of the genital and respiratory tract and it was recently also detected in intestinal mucosa. Furthermore an earlier study showed high concentrations of SLPI in peritoneal fluid from patients with perforations of the large and small intestines. As SLPI is acid-stable, this raised the question of to what extent swallowed SLPI may contribute. The present study investigated the turnover of swallowed SLPI in the gastrointestinal tract. Native 125I-labelled SLPI was instilled in the duodenum of three healthy volunteers and radioactivity in plasma, faeces and urine was measured. Within 72 h 81.4% of the injected radioactivity was excreted in urine and 3.6% in faeces as radioactive low molecular weight proteins (< 1 kDa). Recombinant human SLPI (rh-SLPI) was incubated with porcine pepsin or human gastric or duodenal juice. This resulted in rapid degradation of SLPI to smaller molecules. In conclusion, SLPI is rapidly degraded in the stomach and duodenum. There were no measurable amounts of SLPI in the faeces. We have shown that during normal conditions, swallowed SLPI was rapidly degraded in the stomach and duodenum, and therefore it probably can not be of any importance for inflammatory diseases in the intestines.