Prednisolone produced gastric ulcers in all the experimented animals. Acidity of the gastric content was not increased after prednisolone but actually a reduction of acidity was noted. Atropine, an anticholinergic agent, failed to afford effective protection against prednisolone induced gastric lesion in rats. It thus appeared that prednisolone induced gastric lesion in rats did not involve any hypercholinergic activity. Antazoline, an antihistaminic, also failed to afford effective protection. Moreover, there was no increase in acidity of the gastric contents after administration of prednisolone. On the contrary, acidity was decreased. These findings suggested that histamine may also not be involved in prednisolone induced gastric lesions in rats. Further histamine has also been reported not to be ulcerogenic in rats. Cyproheptadine, a 5 HT antagonist with strong antihistaminic property, afforded effective protection against prednisolone induced gastric lesion in rats. Histamine as already noted is not ulcerogenic in rats. So protection afforded here by cyproheptadine in prednisolone induced gastric ulcer was not due to its antihistaminic action. It is more likely to be due to its antiserotonin action. It was further observed that cyproheptadine also afforded considerable protection against 5 HT induced gastric lesion in rats. The probability thus existed that prednisolone induced gastric lesion was associated with 5 hydroxytryptamine activity. This assumption was further supported by the fact that prednisolone like 5 HT induced the gastric acidity in rats. To study a possibility that 5 HT was involved in the causation of prednisolone induced ulcer, 5 HT content of gastric tissue was estimated in the control group, the prednisolone treated rats, the nialamide treated rats and rats treated with both prednisolone and nialamide. It would appear that there was a considerable fall in the 5 HT content following the administration of prednisolone. This may be due to rapid metabolism of 5 HT released from its bound form which is responsible for the gastric lesion induced by prednisolone. This seemed probable when it was found that administration of the nialamide, a MAO inhibitor markedly increased the 5 HT content of gastric tissue, producing considerable gastric damage at the same time. A further increase in 5 HT content of gastric tissue following premedication with nialamide before the administration of prednisolone strongly indicated that prednisolone released a large quantity of 5 HT from the gastric mucosa which was protected from destruction by the prior administration of MAO inhibitor, nialamide. These findings suggested that prednisolone liberated 5 HT from the gastric tissue in rats. These effects of prednisolone might be responsible for the drug induced gastric lesion in rats.