Two groups, each with nine essential hypertensive patients, were maintained on 10 mmol sodium daily over 14-17 days and treated in this sequence: (1) placebo; (2) captopril (25 or 50 mg given thrice daily) or indomethacin (50 mg given thrice daily) alone; (3) captopril plus indomethacin, and (4) captopril alone. The initial fall in mean blood pressure induced by captopril (118 ±1 to 102 ±1 mmHg) was unaffected by the addition of indomethacin. However, if indomethacin treatment preceded captopil, the antihypertensive effect was attenuated (116 ±4 to 109 ±4), and was associated with significant reductions in urinary prostaglandin and kinin excretion. Addition of captopril to indomethacin returned kinin excretion to placebo levels but did not affect indomethacin-induced reduction in prostaglandin excretion. Captopril alone stimulated plasma renin activity (PRA) fivefold; aldosterone excretion was lowered by 25% and further reduced by indomethacin. Thus, when captopril and indomethacin are administered together, the order of administration is critical to the antihypertensive effect of captopril.