An investigation was made on the effects of histamine and related receptor agonists and antagonists on amylase secretion and Ca2+ mobilization in isolated guinea pig pancreatic segments and acinar cells. The effect of acetylcholine (ACh) was examined for comparison. Histamine evoked marked dose-dependent increases in amylase secretion and small changes in 45Ca2+ efflux, 45Ca2+ influx and intracellular free Ca2+ concentration [Ca2+]i, compared to much larger responses obtained with ACh. The H1 receptor agonist 2-thiazolyl-ethylamine (2-TEA) elicited a small increase in amylase secretion, whereas the H2 receptor agonist dimaprit had little or no effect. Similarly, 2-TEA evoked only small increases in Ca2+ mobilization, whereas dimaprit had no detectable effect. The H2 receptor antagonist oxmetidine also stimulated amylase output in a dose-dependent manner, similar in magnitude to histamine, whereas the H1 receptor antagonist chlorpheniramine (CPR) was only effective as a secretagogue at 10–2 M The H1 antagonist also completely abolished the secretory responses of 2-TEA and markedly reduced the histamine-induced amylase secretion. The results demonstrate the involvement of histamine receptors in the control of amylase secretion and Ca2+ mobilization in guinea pig pancreatic acinar cells.