The aim of this study was to determine whether the injury to the rat jejunum during the first 4.5 h exposure to indomethacin is due to an influx of neutrophils or degranulation of resident mast cells. Indomethacin and vehicle both caused changes in villous morphology (length, width, etc.) while only indomethacin injured the small bowel, as indicated by increased histological lesion score and 51Cr-ethylene diamine tetraacetate (EDTA) flux across the intestinal epithelium. Immunohistochemical staining showed the same small increase in neutrophil density (predominantly in the submucosa) following exposure to vehicle as following exposure to indomethacin. Chronic oral administration of indomethacin for 48 h did cause increased tissue neutrophil density compared to that in vehicle-fed controls. Mast cell depletion (using dexamethasone) did not alter either the indomethacin-induced increase in 51Cr-EDTA clearance or the increase in neutrophil density caused by the vehicle and by indomethacin. However, the lesion score following exposure to indomethacin was significantly lower in mast-cell-depleted animals than in control animals. We conclude that the acute phase of indomethacin-induced intestinal injury is not associated with neutrophil influx. Increased neutrophils seen after chronic indomethacin may result from injury rather than be causative. Mast cells appear to exacerbate the initial stages of indomethacin-induced intestinal injury.