The dinucleotide repeat polymorphism (5'-ALR2) in the promoter region of the aldose reductase gene on chromosome 7q35 has been implicated in the development of diabetic nephropathy in Type I (insulin-dependent) diabetes mellitus, and markers flanking the aldose reductase locus have given evidence suggestive of a linkage between diabetic nephropathy and Type II (non-insulin-dependent) diabetes mellitus in Pima Indians. To examine whether the 5'-ALR2 polymorphism in the aldose reductase gene is involved in the development of diabetic nephropathy in Caucasians with Type II diabetes, we carried out a large association study. Patients with Type II diabetes from one outpatient clinic were screened for diabetic nephropathy and divided into three groups according to the degree of this disease: 179 patients with normoalbuminuria, 225 patients with microalbuminuria and 70 patients with proteinuria. Patients with normoalbuminuria were included in the study only if they had had Type II diabetes for 10 or more years. DNA from all patients was genotyped for the 5'-ALR2 polymorphism using a previously established polymerase chain reaction protocol. The frequency of the putative risk allele Z-2 was 34.6%, 34.2% and 33.6% in the normoalbuminuria, microalbuminuria and proteinuria groups, respectively. Similarly no difference among groups was found for the frequency of the putative protective allele Z + 2. In conclusion, the results of our association study in Caucasian patients with Type II diabetes do not support the hypothesis that the 5'-ALR2 polymorphism in the aldose reductase gene contributes to susceptibility to diabetic nephropathy.