Ondansetron (0.08, 0.15 or 0.3 mg/kg) injected s.c., every 12 h with the fourth dose given 0.5 h before experiments, dose-dependently lessened gastric glandular mucosal ulceration produced by cold-restraint stress for 2 h. When given intracerebrally (i.c.) (0.1, 0.5 or 1 microgram), using the same treatment regimen, infusion of ondansetron 1 microgram into the nucleus amygdaloideus centralis decreased stress-evoked ulcers; in contrast, injection of the same dose into the nucleus accumbens intensified these lesions. The associated stress-induced stomach wall mast cell degranulation was unaffected by all s.c. or i.c. doses of ondansetron. Pretreatment with disodium cromoglycate i.p. alone, or concurrently with ondansetron s.c., prevented not only ulceration but also mast cell degranulation. 5-Hydroxytryptamine3 receptor antagonism appears to inhibit stress-evoked ulcers mainly by blocking the peripheral effects of the amine after its release from the gastric mucosal mast cells.