The interactions between ethanol (EtOH) and acetylsalicylic acid (ASA) in damaging the gastric mucosa were investigated in urethane-anaesthetised rats upon intragastric irrigation. The addition of 5, 10 or 20 mM ASA to 1 and 4 M EtOH instillates strongly aggravated lesion formation in the gastric mucosa and mucosal bleeding. ASA enhanced the back-diffusion of hydrogen ions into the mucosa induced by 1 M EtOH, whereas gastric mucosal blood flow, which is thought to dispose of the back-diffused acid from the mucosa, remained unchanged, thus resulting in an accumulation of acid within the gastric mucosa. ASA did not further enhance the strongly increased back-diffusion of hydrogen ions induced by 4 M EtOH, but it effectively inhibited EtOH-induced stimulation of the gastric mucosal blood flow, thus causing an increase in the ratio between hydrogen ion back-diffusion and gastric mucosal blood flow. The simultaneous presence of EtOH and ASA did not enhance the rates of absorption of each from the instillates. The results indicate that EtOH and ASA have a strong synergistic action in damaging the gastric mucosa in the rat. The mechanism of this interaction may be an increased accumulation of hydrogen ions within the gastric mucosa, resulting in excessive acidification of the mucosal tissue.