Hydrocele is a build-up of fluid in the scrotal regions of a proportion of men infected with the filarial nematode Wuchereria bancrofti. Vascular endothelial growth factors (VEGF) are major mediators of vascular permeability and angiogenesis in the development and progression of many diseases, making them candidates in hydrocele development. We assessed the role of VEGF-A genetic polymorphisms in hydrocele development in a cohort of lymphatic filariasis patients from Ghana. Three VEGF-A promoter polymorphisms were examined. The C/C genotype at -460 was significantly higher in hydrocele patients ([P = 0.0007], OR = 3.8 [95% CI = 1.9-8.2]) than in non-hydrocele patients. Furthermore, plasma levels of VEGF-A were significantly higher in subjects with the C/C genotype than in those with other genotypes. Also, a positive correlation (R(2) = 0.412, P = 0.026) was observed between plasma VEGF-A and stage of hydrocele. The data suggest that the C polymorphism at -460 is a genetic risk factor for hydrocele development in lymphatic filariasis.