Vascular endothelial growth factor (VEGF) is a cytokine involved in angiogenesis and is closely related to the nitric oxide-cyclic guanosine monophosphate pathway, a target for sildenafil. We investigated for the first time whether three clinically relevant polymorphisms in the VEGF gene are associated with altered responsiveness to sildenafil treatment in postoperative erectile dysfunction (PED) and clinical erectile dysfunction (CED). We determined VEGF genotypes for three polymorphisms in VEGF promoter: -2578C>A (rs699947), -1154G>A (rs1570360) and -634G>C (rs2010963) in 126 patients with erectile dysfunction (ED; 66 patients with PED and 60 patients with CED). The patients were classified as good or poor responders to sildenafil (GR and PR groups, respectively) according to their responses with basis on the changes in five-item version of the International Index for Erectile Function (5-IIEF). We found an association of the -1154AA genotype with PR in both PED and CED patients (P<0.05), whereas the -2578AA and the -2578CA genotypes were associated with PR only in the CED group (P<0.05). The AAG haplotype was more common in PR than in GR patients (38% versus 20%, respectively; P=0.032) in the CED group, thus increasing the risk for a worse response to sildenafil (odds ratio, OR=2.33, 95% confidence interval, CI=1.07-5.09). However, this finding does not resist to Bonferroni's correction (P>0.0125). Our results indicate that VEGF polymorphisms affect the responsiveness of PED and CED patients to sildenafil. These findings may help to improve the therapy of patients with ED.