Differences between prostaglandins I₂ and E₂ in their renal synthesis and pathophysiological roles were investigated in unilateral renovascular hypertension of different severities in 18 patients: 6 with mild stenosis (<75% of the diameter) of the renal artery, 7 with moderate stenosis (75% to 90%), and 5 with severe stenosis (>90%). Before and after aspirin administration (10 mg/kg), renal venous and aortic plasma was assayed for 6-ketoprostaglandin F_1α (instead of prostaglandin I₂), prostaglandin E₂, and renin activity. In mild or moderate stenosis, the mean 6-ketoprostaglandin F_1α level in renal venous plasma from the stenotic side was not different from that from the normal side or from aortic plasma. Prostaglandin E₂ levels and renin activity in such patients were higher on the stenotic side than on the normal side and higher in venous than in aortic plasma. Aspirin inhibited prostaglandin E₂ synthesis and suppressed renin release from stenotic kidneys and lowered blood pressure as the renin activity decreased in patients with mild or moderate stenosis. In severe stenosis, levels of 6-ketoprostaglandin F_1α and prostaglandin E₂ were higher on the stenotic side than on the normal side and higher in venous than in aortic plasma. Aspirin inhibited the synthesis of both prostaglandins and suppressed renin release from the stenotic kidney. In patients with unilateral renovascular hypertension with mild or moderate stenosis of the renal artery, prostaglandin E₂, rather than I₂, seems to contribute to further acceleration of renin release. Prostaglandin I₂ may increase and participate in further renin release when the stenosis is severe.