The effects of acid, acetylsalicylic acid (aspirin), and ethanol in damaging the gastric mucosa, and in particular in causing hemorrhage, were studied by irrigating pouches of the oxyntic glandular area of the dog's stomach with solutions containing 54 MN NaCl and combinations of acid (0, 1, 10, or 100 MN HC1), aspirin (0, 5, 10, or 20 mm), and ethanol (0, 4 to 5, or 8 to 10% w/v). Zero acidity (pH 6.2 to 7.4) was achieved using either citrate or Tris buffer; the results were the same with either buffer. Rates of absorption of aspirin and ethanol were measured, and the rate of absorption of one was found to be entirely independent of the other. Net Na+ and H+ fluxes during subsequent irrigation with 100 MN HCl plus 54 MN NaCl were measured and compared with fluxes observed during control periods to assess changes in the gastric mucosal barrier. Rate of bleeding was measured by hemoglobin output. Although aspirin is slowly absorbed from neutral solutions, the mucosa never bled during irrigation with aspirin in neutral solutions with or without ethanol, nor did it bleed when it was subsequently irrigated with 100 MN HC1. Irrigation with 20 mm aspirin in 1 or 10 MN HC1, with or without ethanol, always damaged the gastric mucosal barrier as shown by increased net Na+ fluxes. The mucosa did not bleed during irrigation with these solutions, but it usually bled when subsequently irrigated with 100 MN HCl or when it was stimulated to secrete by injection of histamine or bethanechol chloride. Severe damage and brisk bleeding were always produced by the combination of 20 mm aspirin, 100 MN HC1, and 8 to 10% ethanol. Solutions containing 4 to 5% ethanol; 10 or 20 mm aspirin; and 1, 10, or 100 MN HCl were more damaging than the corresponding solutions containing no ethanol. The threshold concentration of acid required to produce bleeding after exposure of the mucosa to aspirin, acid, and alcohol was determined by irrigating the mucosa first with 20 mm aspirin in 10 MN HCl and 8 to 10% ethanol and then with 10, 25, 40, or 65 MN HC1. The acid threshold for bleeding lay between 25 and 65 MN HC1. Irrigation of bleeding pouches with either citrate- or Tris-buffered neutral solutions nearly always resulted in cessation of bleeding within 75 min, and recovery from bleeding was the same whether or not the neutral solutions contained 20 mm aspirin.