The interaction of indomethacin and aspirin or mepirizole was studied in rats. Concomitant oral administration of aspirin and indomethacin had no significant influence on the gastro-ulcerogenicity of indomethacin alone, but caused significantly less intestinal damage than an identical dose of indomethacin alone. In proportion to the inhibitory activity of intestinal lesions, aspirin also showed the activity that antagonized significantly the shortening of small intestinal length, loss of body weight and delay of charcoal transport in the intestine induced by indomethacin alone. Aspirin tended to reduce also the anti-inflammatory and analgesic effects of indomethacin in combined administration. On the other hand, mepirizole significantly reduced both gastric and intestinal ulcerogenicities by indomethacin alone in concomitant oral administration and inhibited dose-dependently the incidence and severity of those lesions. The inhibitory activity of gastrointestinal lesions by mepirizole was in proportion to the activities that antagonized the shortening of the small intestine, loss of body weight and delay of charcoal transport by indomethacin. Moreover, in contrast to aspirin, mepirizole exerted more potent anti-inflammatory and analgesic effects in combined administration than in the single administration of indomethacin. Therefore, aspirin reduced both the intestinal side effect and the anti-inflammatory effect induced by indomethacin in combination, while the combination of mepirizole reduced the gastrointestinal side effects by indomethacin alone, but seemed to be additive in the anti-inflammatory effect.