Recent studies suggest that the gene encoding aldose reductase (ALR2), the enzyme that converts glucose to sorbitol, may confer susceptibility to microvascular disease. DNA from 275 British Caucasian patients with type I diabetes and 102 normal healthy control patients were typed for a (CA)n dinucleotide repeat polymorphic marker in the 5'-region of the ALR2 gene using polymorase chain reaction (PCR). A highly significant decrease in the frequency of the Z+2 allele was found in patients with nephropathy (nephropathy group) compared with those with no complications after a 20-year duration of diabetes (uncomplicated group) (12.7 vs. 38.2%, respectively, chi2 = 18.6, P < 0.00001); this was accompanied by an increase in the Z-2 allele in the nephropathy group (32.0 vs. 12.7% in the uncomplicated group). The nephropathy group also had a significant decrease in the Z/Z+2 genotype compared with the uncomplicated patients (10.7 vs. 44.7%, chi2 = 16.0, P < 0.0001) and an increased frequency of the Z/Z-2 genotype. There was no significant association with diabetic retinopathy. These results demonstrate that the ALR2 gene may play a role in susceptibility to diabetic nephropathy; individuals with the Z+2 allele are more than seven times less likely to develop diabetic renal disease than those without this marker. This marker may prove valuable in screening for patients with diabetic nephropathy at diagnosis of diabetes.