This study examines the effects of histamine on mucosal permeability to acid by isolated stomach of rabbits. Histamine (9 X 10(-5) M) decreased antral luminal acid loss which could not be accounted for by active H+ secretion or appearance of organic acid. Histamine also increased antral electrical resistance and decreased the unidirectional luminal to serosal flux (Jls) of (14)c-erythritol. Histamine, theophylline, and N(6),O(2)-dibutyryl adenosine 3',5'-monophosphate did not significantly alter secretion by fundus in the presence of salicylate (5 X 10(-3)M). However, after removal of salicylate, these agents stimulated acid secretion. Histamine decreased luminal acid loss by both antrum and fundus treated with salicylate, increased the electrical resistance of these tissues, and decreased Jls erythritol of fundic mucosa. Burimamide (1 X 10(-3) M) inhibited the permeability effects of histamine on antrum and fundus. The data indicate that histamine decreases spontaneous antral mucosal permeability as well as salicylate-induced increase in mucosal permeability of both antrum and fundus. The effects of burimamide suggest that antrum contains H2 receptor sites urelated to acid secretion and that fundus contains H2 receptor sites which also govern permeability but are independent of those related to acid secretion.