Curcuma longa has been commonly used as a traditional remedy for a variety of symptoms such as inflammation, gastritis and gastric ulcer. When C. longa extract was administered per os to pylori-ligated rat stomachs, it reduced gastric acid secretion and protected against the formation of gastric mucosal lesions. We therefore tested whether C. longa extract inhibits gastric ulcers by blocking the H2 histamine receptor. Dimaprit, a H2 histamine receptor agonist, induced intracellular cAMP production in U937 and HL-60 promyelocytes. Pretreatment with C. longa extract significantly blocked dimaprit-induced cAMP production in a concentration dependent manner, but had no effect on the elevation of cAMP levels triggered by isoproterenol-induced β2-adrenoceptor activation in U937 cells. To identify the active component(s) of C. longa extract, we sequentially fractionated it by extraction with ethyl acetate, n-butanol and water. We found that the ethyl acetate extract showed the most potent H2R antagonistic effect against dimaprit-induced cAMP production. However, curcumin, a major component of C. longa extract, showed no H2R blocking effect. C. longa ethanol extract and ethylacetate extract also blocked the binding of [3H]-tiotidine to membrane receptors on HL-60 cells. These findings suggest that the extract from C. longa specifically inhibits gastric acid secretion by blocking H2 histamine receptors in a competitive manner.