Recombinant human lactoferrin (RHLF) was tested for its ability to prevent non-steroidal anti-inflammatory drug (NSAID)-induced intestinal injury in rats and mice. Acute and chronic models using indometacin, naproxen and diclofenac were used. Measurements were made of intestinal bleeding and inflammation. Orally administered RHLF was effective at preventing acute NSAID-induced increases in gut bleeding and myeloperoxidase activity. Oral RHLF was also effective at blocking some chronic manifestations of indometacin usage. Protection by RHLF of the intestinal tract from NSAIDs appears to be linked to attenuation of neutrophil migration to the intestine, and is independent of prostaglandins and nitric oxide. RHLF does not bind to the NSAID or interfere with the NSAID biological activity. We conclude that orally administered RHLF is effective at preventing NSAID-induced intestinal injury in rodents and should be investigated for this potential therapeutic use in man.