We report testing of the suggestion that aggravation of the actions of glucocorticoid treatment on the formation of indomethacin-induced erosions may be mediated by inadequate production of glucocorticoid hormones resulting from the suppression of the hypothalamo-hypophyseal-adrenocortical system (HHACS) in these conditions. Administration of indomethacin (25 mg/kg, s.c.) to rats after 24 h of starvation was used to induce gastric erosions. The effects of hydrocortisone given at pharmacological doses on the indomethacin-induced formation of gastric erosions and plasma corticosterone levels were studied one and four weeks after hormone administration. Indomethacin induced increases in plasma corticosterone levels, which were almost completely prevented one week after hydrocortisone administration. The formation of indomethacin-induced erosions was aggravated one week after administration of hydrocortisone, though replacement therapy with corticosterone, which imitates the normal increase in corticosterone, prevented this aggravation. Return of both the increased corticosterone level and the normal sensitivity of the gastric mucosa to the ulcerogenic action of indomethacin occurred four weeks after hydrocortisone administration. These results provide evidence that suppression of HHACS function may be responsible for the aggravation of the action of glucocorticoid treatment on the formation of erosions after administration of indomethacin.