Infection with Helicobacter pylori and the use of non-steroidal anti-inflammatory drugs (NSAIDs) are recognized as the two primary factors in the etiology of gastric disease. In this study, we applied the animal model of H. pylori-induced gastritis to assess the influence of NSAIDs on the course of mucosal inflammatory responses to H. pylori. Two days following intragastric application of H. pylori lipopolysaccharide, rats were divided into groups and administered daily for up to 8 days either indomethacin, aspirin or the vehicle, and their gastric mucosal tissue subjected to histological and biochemical assessment. H. pylori lipopolysaccharide elicited within 2 days a pattern of acute mucosal inflammatory responses accompanied by a massive epithelial cell apoptosis, and a marked increase in the expression of membrane-bound and soluble forms of TNF-alpha. The extent of mucosal inflammatory involvement reached a maximum by the 4th day and showed a decline by the 10th day; this was reflected in a 38.1% reduction in apoptosis, a 53.2% decline in membrane-bound TNF-alpha and a 63.8% decrease in soluble TNF-alpha. Compared to the vehicle controls, aspirin caused a 36.2% increase in the severity of the mucosal inflammatory involvement by the second day of administration and a 25.9% increase in the inflammatory involvement occurred by the 8th day; this effect of aspirin was accompanied by a significant (54.5%) induction in apoptosis, a 58.2% decline in membrane-bound TNF-alpha and a 61% increase in soluble TNF-alpha. In contrast, administration of indomethacin evoked only a marginal increase (5-7%) in apoptosis, and caused no discernible changes in the severity of gastric mucosal involvement and the expression of TNF-alpha forms elicited by H. pylori lipopolysaccharide. The findings indicate that aspirin, but not indomethacin, increases the severity of gastric mucosal inflammatory responses to H. pylori. This detrimental influence of aspirin appears to result from up-regulation in the mucosal expression of soluble form of TNF-alpha, which leads to the amplification of apoptotic events that potentiate gastric mucosal inflammatory reaction to H. pylori.