In the last several years, it has been proposed that neutrophil- and oxygen-dependent microvascular injuries may be important factors in the gastrointestinal toxicity of nonsteroidal antiinflammatory drugs (NSAIDs). In addition, after oral administration, reduced levels of gastric mucosal adenosine triphosphate in response to mitochondrial damage constitute the earliest event on topical mucosal erosions. In these experiments, we compared the implication of active oxygen, lipid peroxidation levels and neutrophil infiltration in gastric mucosal injury induced by the analgesic-antipyretic drugs, dipyrone (pyrazolone derivative) and acetaminophen (nonacidic drug), both with relatively weak antiinflammatory effects, with diclofenac (an acidic NSAID). After 6 hr of oral administration, dipyrone (120 and 500 mg/kg) did not provoke macroscopic lesions on rat gastric mucosa. Only the highest dose (1000 mg/kg) induced slight erosions similar to the same dose of acetaminophen without modifications in lipid peroxidation levels or myeloperoxidase activity. The area of mucosa with lesions, the increase in neutrophil infiltration, and concentration of TBA-reactive substances was significantly higher with diclofenac (50 mg/kg). By contrast, inhibition in superoxide dismutase activity was observed. In a dose-dependent manner, dipyrone and diclofenac decreased the levels of endogenous gluthatione, and the highest dose (1000 mg/kg) also inhibited glutathione peroxidase activity. None of treatments induced changes in xanthine oxidase activity, an index of ischemic condition. These findings confirm the favorable gastric tolerability of dipyrone, since only the highest dose produced weak mucosal lesions similar to that obtained with acetaminophen, and this effect only could be related to a diminished glutathione metabolism. In contrast, diclofenac induced significant erosions, and the data obtained indicate that the enhancement of oxidative stress plays an important role in the pathogenesis of damage.