Nephropathy is a frequent complication of long-term diabetes. Strong evidence exists that genetic predisposition plays a major role in the development of diabetic nephropathy. The role of the angiotensin I-converting enzyme gene (ACE) in the susceptibility to nephropathy in diabetes, especially in non-insulin dependent diabetes mellitus (NIDDM), remains unclear. This study examines the association of two ACE polymorphisms: a 287-bp insertion/deletion (I/D) in intron 16 and PstI (A/G substitution in intron 7; alleles P/M) with renal complications in 941 NIDDM patients. From this group, for further analysis 127 patients were selected with overt proteinuria or chronic renal failure, 335 patients with microalbuminuria, and a control group of 254 normoalbuminuric patients with a diabetes duration of at least 10 yr. No significant differences in the distribution of ACE I/D and PstI genotypes or allele frequencies were observed between the examined groups. The results of this study strongly suggest that there is no association between the ACE gene I/D and PstI polymorphisms and nephropathy in NIDDM.