The activity of the renin-angiotensin-aldosterone system (RAAS) plays an important role in the development and progression of diabetic nephropathy. However, the effect of angiotensin-converting enzyme (ACE) inhibition on the RAAS appears to be modulated by a number of factors including the I/D polymorphism of the ACE genotype. In this study, we attempted to find independent correlates of ACE activity in 121 macroalbuminuric type 2 diabetic Iranian patients under chronic ACE inhibition. Both univariate and multivariate analyses were used. The presence of the D allele was independently associated with significantly higher levels of ACE activity (with the II genotype as reference, P < 0.001, B = 27.3, 95% CI = 17.6-37.1), and this association was not eliminated by potentially confounding variables. In conclusion, the D allele is a significant independent correlate of ACE activity in macroalbuminuric type 2 diabetic Iranian patients under long-term ACE inhibition.