Cloxacepride, a potent inhibitor of passive cutaneous anaphylaxis (PCA) in the rat, was evaluated for in vitro inhibitory effect on 48/80-induced histamine and serotonin release from rat mesenterial mast cells. Significant inhibition and linearity of concentration and effect was found in the concentration range of 10 to 50 microM. The IC50 was determined to 21 microM (histamine) and 19 microM (serotonin). A simultaneous liberation of both mediators from mast cells is indicated from nearly identical IC50. LDH increase in the supernatant of the incubation mixture by cell damage resulted from higher concentrations of cloxacepride (greater than 50 microM). The high concentration of 10 micrograms/ml releaser 48/80 did not affect or diminish the effect of cloxacepride, while the reference compounds cromolyn sodium (DSCG) and theophylline were inactive under these conditions. The substantial inhibition of the PCA reaction and of the mediator release from mast cells provides cloxacepride a promising potential antiallergic drug.