Several studies have shown genetic predisposition for diabetic complications. The leucine7 to proline7 (Leu7Pro) polymorphism of preproNPY has been shown to be a risk factor for diabetic retinopathy in type 1 diabetes. In the current study we examined the contribution of this polymorphism on the progression of retinopathy in Caucasian type 1 and type 2 diabetes patients. Patients with type 2 diabetes and the Leu7Pro polymorphism developed retinopathy at younger age because of markedly earlier disease onset of diabetes (RC- 6.8, 95% CI-12.2 - [- 1.5]), but no association of the Leu7Pro polymorphism with the current severity of retinopathy was detected. A strong association of the polymorphism with proteinuria in type 2 diabetes patients with retinopathy could be detected (OR 3.1, 95% CI 1.1-8.8); 31% of subjects having both retinopathy and proteinuria had the polymorphism compared to only 13% of retinopathy patents without concomitant proteinuria (p = 0.032). Plasma concentrations of NPY were increased in subjects with proteinuria (79.2+/-28.4 and 64.7+/-26.2 pmol/l, p = 0.001). These results suggest that the Leu7Pro polymorphism could be used to predict earlier onset of type 2 diabetes and retinopathy, and increased risk for diabetic nephropathy.