SUMMARY The H2-receptor antagonist, cimetidine, reduces acid output regardless of the means of stimulation. It is not known in man whether this is due entirely to a reduction in acid secretion or whether increased back diffusion of hydrogen ions is also occurring. We studied fluxes of H+, Na+, K+, and Cl -ions after acid instillation into the human stomach in six healthy subjects with and without prior administration of 300 mg cimetidine orally. Potential difference across gastric mucosa was measured continuously throughout each study. Cimetidine caused a significant reduction in hydrogen ion secretion (5 05 mEq per 15 minutes controls versus 2-70 cimetidine, P < 0 05), and consequently a significant reduction in net hydrogen flux into the gastric lumen (2'01 mEq per 15 minutes versus 0-02, P < 0 05). There were no significant differences between sodium ion fluxes in control and cimetidine studies, suggesting that the gastric mucosal barrier remained intact. Cimetidine alone caused a highly significant rise in intragastric pH (to 7) and of potential difference (P < 0 001). Addition of intragastric acid (pH < 1 -0) did not reverse the rise in potential difference caused by cimetidine, suggesting that factors other than change in intragastric pH were involved. In conclusion, our studies support the concept that reduction in acid output by cimetidine is due to inhibition of acid secretion, and not to increased permeability to hydrogen ion.Changes in acid secretion cannot satisfactorily explain gastric mucosal damage associated with conditions such as gastric ulcer or acute aspirininduced mucosal damage. The ill-defined concept of mucosal resistance has long been used to explain such cases. An attempt to define and measure this resistance objectively was the 'gastric mucosal barrier' concept popularised by Davenport (1970); Ivey (1971); Code et al. (1963);and Reitemeier et al. (1957). Davenport found that topical aspirin induced an increase in the net fluxes of Na+ ions into the gastric lumen and at the same time of H+ ions out. Increased net movement of Na+ ions into the lumen and of H+ ions out was termed 'alteration' or 'damage' to the 'gastric mucosal barrier' which limited potentially damaging H+ ion movement into the gastric mucosa. In Davenport's studies, alteration of net Na+ and H+ fluxes was associated with a fall in PD. Other workers (Chvasta and Cooke, 1972) confirmed this, and so changes in PD became "Address for reprint requests: Kevin J. Ivey,