Recently we have reported that ethane dimethane-sulphonate (EDS), the Leydig cell cytotoxin, caused marked atrophy of the adrenal cortex of adult male rats. The aim of this work was to examine whether a 9-day treatment with dexamethasone (0.25 mg/kg/d) or ACTH (40 IU/kg/d), which started 4 days prior to administration of a single dose of EDS (75 mg/kg), influenced the response of the inner adrenocortical zones to the toxin. On day 15 after administration of EDS, adrenal weight was significantly decreased in saline treated rats, but glandular and serum corticosterone levels were not altered. In dexamethasone-suppressed rats, the effect of EDS was augmented; an additional decrease in adrenal weight was accompanied by reduced adrenal and serum corticosterone levels. In ACTH-treated animals EDS was ineffective. These results demonstrate that the deleterious effects of EDS on rat adrenal cortex can be prevented by ACTH and potentiated by dexamethasone.