Activation of histamine H 3 receptors by histamine (0.1 to 10 μM), (R)α-methylhistamine and N α -methylhistamine (0.01 to 0.3 μM) was shown to inhibit cholinergic nerve transmission in the guinea-pig ileum. Iodoaminopotentidine (IAP 300 nM), a potent H 2 receptor antagonist, was found to decrease this effect but had no significant effect (P>0.05) on contractile responses produced by exogenous acetylcholine (0.2 μM). Dimaprit (0.1 to 10 μM) an H 2 receptor agonist/H 3 receptor antagonist, produced no significant effect (P>0.05) on the response to cholinergic nerve stimulation but reduced the effect of N α -methylhistamine. Furthermore, ranitidine (10 μM) an H 2 receptor antagonist did not modify the inhibitory effect of histamine. These results suggest that IAP may inhibit H 3 receptors in the ileum at similar concentrations reported to inhibit H 2 receptors in functional studies.