Thapsigargin is a potent skin irritating sesquiterpene lactone isolated from the roots of Thapsia garganica L. (Apiaceae). In rat peritoneal mast cells thapsigargin induced a calcium-dependent non-cytotoxic [C]arachidonic acid and histamine release. A minor amount of the released [C]arachidonic acid was converted to [C]prostaglandin D. A potentiated effect was found between thapsigargin and 12--tetradecanoylphorbol 13-acetate, as well as between A23187 and the phorbol ester with respect to release of [C]arachidonic acid and histamine. It is suggested that the synergistic effect is due to activation of protein kinase C by 12-O-tetradecanoylphorbol 13-acetate and to increased intracellular calcium concentration mediated by A23187 as well as thapsigargin. [C]arachidonic acid was released mainly from phosphatidylcholine. It is suggested that this release may be due to an action of phospholipase A, and that protein kinase C is involved in activation of phospholipase A.