Background: Endothelial nitric oxide synthase (eNOS) is essential in chronic inflammation and carcinogenesis. The association between variants in vascular endothelial growth factor (VEGF) and several cancers still remains uncertain. We studied whether there is a relation between eNOS/VEGF variants and risk of pancreatic cancer (PC). Materials and Methods: This prospective case-control study included 76 PC patients (28 women and 48 men) and 100 healthy controls. Blood samples from all participants were genotyped for eNOS variable number tandem repeat (VNTR) and VEGF insertion/deletion (I/D) variants by PCR. Results: There was a significant difference between groups for the eNOS intron 4 VNTR genotype distributions (p = 0.01). eNOS 4a/4b and 4b/4b genotypes were higher in patients with PC group compared to controls while eNOS 4a/4b genotype was more prevalent in control group than in patient group. Significant differences were observed between groups for the VEGF I/D variant genotype and allele frequencies (p < 0.00, and p < 0.00). VEGF I/D variant I/I genotype and I allele increased in patient group than controls. A statistically significant association was observed when the patients were compared with the controls according to D/D + D/I versus D/D (p < 0.00, OR: 0.094, 95% CI: 0.03-0.22). Conclusions: We provided evidence that eNOS VNTR and VEGF I/D variants might influence the development of PC.