Autosomal-dominant polycystic kidney disease (ADPKD) is one of the most common monogenic diseases. It is characterized by a substantial variability in the severity of renal phenotype, primarily assessed by the age at end-stage renal disease (ESRD). The role of modifier genes has been shown in various hereditary diseases, including ADPKD. The gene coding for the endothelial nitric oxide synthase (NOS3) is considered to have a modifier effect on the severity of ADPKD, even if there are studies among different populations that have shown contradictory results. In this study, we investigated the influence of one of the most studied polymorphisms of the NOS3 gene, the Glu298Asp polymorphism, on the age at ESRD in ADPKD. We analyzed a total of 100 ADPKD unrelated patients and 107 healthy cohorts from the Greek population. ADPKD patients were classified into two subgroups: patients with early (rapid progressors) and late (slow progressors) age at ESRD. The results suggested that the Glu298Asp polymorphism of NOS3 gene is associated with the onset age of ESRD. The distribution of C/T alleIes is significantly different between rapid and slow ADPKD progressors leading to the conclusion that the T allele of the Glu298Asp polymorphism of NOS3 gene is associated with earlier progression to ESRD in ADPKD patients.