The present study was designed to examine the effects of a sesquiterpene lactone isolated from Artemisia douglasiana Besser (dehydroleucodine, DhL), a xanthanolide sesquiterpene isolated from Xanthium cavanillesii Schouw (xanthatin, Xt) and a semisynthetic butenolide (3-benzyloxymethyl-5H-furan-2-one, But) on mast cell histamine release induced by compound 48/80. Peritoneal mast cells from male adult Sprague-Dawley rats were purified in Percoll, preincubated in the presence of test lactones (DhL, Xt or But) and then challenged with the mast cell activator compound 48/80. Concentration-response studies of mast cell histamine release evoked by compound 48/80, evaluation of mast cell viability and morphology studies by light microscopy were carried out. Biochemical and morphological studies showed the effectiveness of the above lactones to inhibit secretory responses of rat peritoneal mast cells. The present study provides evidence in favor of the hypothesis that DhL, Xt and But inhibit compound 48/80-induced histamine release from rat peritoneal mast cells. Our findings may provide an insight into the design of novel pharmacological agents that may be used to regulate the mast cell response.