AbstractAims  The aldose reductase gene (AKR1B1) is a strong candidate for diabetic nephropathy, and the T allele at rs759853 and the Z‐2 allele at an [AC]n microsatellite are associated with diabetic kidney disease in some populations. As AKR1B1 is located on 7q35, where we have previously reported linkage to diabetic nephropathy in Pima Indians, this study examined the association of AKR1B1 variants with diabetic nephropathy in this population.Methods  AKR1B1 variants were identified by sequencing and genotyped using allelic discrimination and pyrosequencing. Genotype distributions were compared between 107 cases with diabetic end‐stage renal disease and 108 control subjects with diabetes for ≥ 10 years and no evidence of nephropathy, and between 141 individuals with nephropathy and 416 individuals without heavy proteinuria in a family study of 257 sibships.Results  We identified 11 AKR1B1 single nucleotide polymorphisms (SNPs) and the [AC]n microsatellite polymorphism. Three SNPs were rare and two were in 100% genotypic concordance; thus, eight polymorphisms were genotyped. No variant was associated with diabetic kidney disease in the case‐control or family‐based study. For example, the T allele at rs759853 had an allele frequency of 0.165 in cases and 0.171 in control subjects (OR = 0.96, 95% CI, 0.57–1.59, P = 0.86); in the family study its frequency was 0.140 and 0.169 in affected and unaffected individuals, respectively (OR = 0.90, 95% CI, 0.53–1.54 P = 0.71). Corresponding values for the Z‐2 allele at the [AC]n microsatellite were OR = 1.09 (95% CI 0.72–1.66, P = 0.67) and OR = 1.25 (95% CI 0.81–1.95, P = 0.31) in the case‐control and family studies, respectively.Conclusions  Common AKR1B1 polymorphisms are unlikely to be major determinants of diabetic nephropathy in this population.Diabet. Med. 23, 367–376 (2006)