OBJECTIVE Parenteral administration of nonsteroidal anti-inflammatory drugs (NSAIDs) may cause gastrointestinal mucosal lesions. The aim of this study was to investigate whether parenteral NSAIDs alter surface hydrophobicity of the gastroduodenal mucosa. METHODS Conscious rats received indomethacin or diclofenac subcutaneously at different doses (0.5-10 mg/kg). Surface hydrophobicity of gastric and duodenal mucosa was determined by contact angle measurement at various time points; mucosal prostaglandin synthesis and mucus phospholipid content were measured. Also, the effects of NSAIDs were studied in bile duct-ligated rats. RESULTS A single 1-2-mg/kg dose significantly decreased hydrophobicity in the stomach and duodenum. The decrease was associated with a reduction in mucus phosphatidylcholine. In the duodenum, mucosal prostaglandin synthesis was restored 24 hours after NSAID dosing, but hydrophobicity was still decreased. There was no adaptation to long-term treatment. In bile duct-ligated rats, NSAIDs did not decrease gastric or duodenal hydrophobicity. Moreover, oral administration of bile from rats pretreated with parenteral NSAIDs significantly decreased mucosal hydrophobicity in untreated rats. CONCLUSIONS Low-dose NSAIDs by parenteral route impair the physicochemical barrier against luminal acidity and render the mucosa susceptible to injury. Excretion of NSAIDs in bile seems to play a key role in this effect.