The antiproteinuric effect of angiotensin I-converting enzyme (ACE) inhibitors in patients with renal diseases of various origins has been well recognized. However, individual responses regarding the degree of decrease in urinary protein excretion appear to vary considerably. The mechanism underlying this variable response to ACE inhibitors has not been clarified yet. A possible role of ACE gene insertion/deletion (I/D) polymorphism in the responsiveness to antiproteinuric effect of ACE inhibitors is examined. Thirty-six patients with proteinuria (23 men and 13 woman; mean age, 47 +/- 13 yr) were studied. These patients were classified into two groups on the basis of the percent decrease in their urinary protein excretion: the effective group, those with a decrease in proteinuria (18 patients, -64 +/- 19%) and the noneffective group (18 patients, +13 +/- 40%). A 287-base pair (bp) I/D polymorphism in the ACE gene was examined by polymerase chain reaction. The allelic frequencies of the ACE gene were I/D = 0.53/0.47 in the effective group and I/D = 0.81/0.19 in the noneffective group. The difference in the allelic frequencies between the two groups was significant (chi 2 = 6.25, P = 0.0114 < 0.05). Furthermore, the difference in the responsiveness of proteinuria to ACE inhibition between genotype II versus genotype ID + DD was statistically significant (chi 2 = 4.05, P = 0.0442 < 0.05). There was no significant difference between the two groups with regard to initial urinary protein level, blood pressure, renal function, and daily sodium intake. The genetic susceptibility to the antihypertensive effect of ACE inhibitors was also studied, but no significant relation was observed. This study suggests the association of ACE gene I/D polymorphism with the antiproteinuric efficacy of ACE inhibitors in patients with proteinuria.