Simple SummaryAs age advances, the risk for developing erectile dysfunction (ED) in men increases. ED can be a mark for cardiovascular diseases, as well as be related to mental disorders such as depression. There are some inherited features that can predict such complications. Therefore, in this study, we investigated whether the variation in the gene that produces the enzyme called nNOS in the body, which is important for maintaining cardiovascular balance, may be related to the risk for the development of ED or the severity of ED. We found that a variant of thenNOSgene may be related to a worse degree of ED. This means that those who have a variation in this region of gene may have a worse degree of ED. Despite the need for confirmation of these data, perhaps these genes can contribute to predicting the risk of this population in developing severe degrees of ED.AbstractErectile dysfunction (ED) is a common male disorder, often associated with cardiovascular disease and ageing. The Sildenafil, a PDE5 inhibitor, can improve the erectile function by prolonging the nitric oxide (NO) downstream effect. NO is a molecule of pivotal importance in erection physiology and is mainly produced by neuronal nitric oxide synthase (nNOS) and endothelial NO synthase (eNOS). While it has been shown thateNOSandnNOSgenetic polymorphisms could be associated with Sildenafil responsiveness in ED, no study so far has assessed whether nNOS polymorphisms andPDE5Apolymorphism could be associated with increased risk to ED or with intensity of symptoms. A total of 119 ED patients and 114 controls were studied, with evaluation of the clinical disability by the International Index for Erectile Function instrument, plasma assessment of nitrite levels and genomic DNA analysis regarding the rs41279104 and rs2682826 polymorphisms of theNOS1gene and the rs2389866, rs3733526 and rs13124532 polymorphisms of thePDE5Agene. We have found a significant association of the rs2682826 with lower IIEF scores in the clinical ED group. While this result should be confirmed in other populations, it may be helpful in establishing a genetic panel to better assess disease risk and prognosis on ED therapy.