The inhibitory effects of emedastine difumarate on histamine release were studied in rat peritoneal mast cells. Emedastine significantly inhibited substance P (SP)-induced histamine release at concentrations above 10(-9) M in the presence of extracellular Ca2+ and at concentrations above 10(-11) M in its absence. At concentrations of 10(-8) M or higher, emedastine significantly inhibited SP-induced Ca2+ release from intracellular Ca stores and SP-induced 45Ca uptake into mast cells. Emedastine also inhibited passive peritoneal anaphylaxis in rats and guinea pigs. We conclude that the clinical antiallergic effects of emedastine involve the inhibition of histamine release and that this inhibition is mediated by the inhibition of Ca2+ release from intracellular Ca stores and the inhibition of Ca2+ influx into mast cells.