Pronounced lesions of the gastric mucosa were induced by Compound 48/80 (1.0 mg/kg, i.v.) in rats protected from lethal shock of released histamine by the experimental histamine H1‐antagonist R 37 617. The intensity score of the lesions correlated with serum pepsinogen levels. Generally the stomachs were greatly distended and contained blood and regurgitated food residues. Compounds from many different pharmacological classes were tested in this procedure. Complete protection was obtained with serotonin antagonists. Also isoproterenol and salbutamol fully protected, apparently by counteracting the serotonin‐induced circulatory stasis. No obvious effect was obtained with antagonists of acetylcholine, dopamine, and histamine, with α‐ and β‐adrenergic blocking agents, with narcotic analgesics, and with various other agents unless doses were administered that by far exceeded the range of their primary activity. The lowest ED50 of ketanserin for protection was 0.15 mg/kg (time—2 hr, both s.c. and p.o.), indicating its high oral effectiveness against venoconstriction induced by endogenous serotonin. These doses also abolished cyanosis and reduced stomach distension, abnormal gastric contents, and serum pepsinogen levels. In view of the recently elucidated differences between serotonin antagonists, the mast cell 5‐HT gastric lesion test appears appropriate to measure the peripheral serotonin S2‐antagonism of compounds.