SUMMARY To compare the sodium-retaining action and the effect on blood pressure (BP) of certain steroids, nine nonnotensive subjects were given fludrocortisone0.3ragorally twice a day (b.i.d.), five received deoxycorticosterone acetate (DOCA) 10ragIM b.i.d., and this was compared to the effect of fludrocortisone or DOCA plus prostaglandin inhibition (PI) or PI given alone. PI was accomplished with either indomethacin 50 mg or ibuprofen 400 mg every 6 hours. All patients received 250 mEq Na+daily. Fludrocortisone alone caused a cumulative Na + balance of 305 ± 46 (SE) mEq and weight gain 2.5 0.1 kg with escape by Day 7. Mean blood pressure (MAP) increased 9 ± 2 mm Hg in both supine and standing positions by Day 8. When fludrocortisone was continued for 16 days, BP rose 14 ± 1 and 11 ± 1 mm Hg respectively. DOCA caused similar Na+retention of 485 ± 125 mEq, weight gain 2 kg, and escape by Day 7; however, no change in BP was observed. PI alone caused retention of 125 ± 49 mEq, weight gain 1 kg, and escape by Day 4, but no change in BP. In contrast, fludrocortisonewith PI added on Day 9 increased BP 21 ± 2 supine (p< 0.01) and 19 ± 2 mm Hg standing (p< 0.001) compared with fludrocortisone alone, but no greater change in Na + or weight was observed. DOCA plus PI also resulted in no greater Na + retention or change in weight than DOCA alone; however, BP increased from 86 ± 3 to 98 ± 2 mm Hg (p< 0.01). Similar suppression in PRA and aldosterone was noted in all of the study groups. We conclude that: 1)fludrocorticonehas a pressor action in normal humans Independent of its effect on sodium balance; 2) DOCA, a pure mineralocorticoid, does not alter BP when given for a period of weeks; 3) PI in normal humans causes some retention sodium, but does not alter BP; 4) prostaglandin synthesis inhibitors potentiate the pressor action offludrocortisoneand raise BP in DOCA-treated humans, suggesting that vascular prostaglandins play a modulating role in BP control.