The high degree of vascularisation, accompanied by the low malignancy of human Leydig cell tumours, offers an interesting model to study the neovascularisation and structural stabilisation of the vascular wall. We report here that Leydig cell tumours are characterised by an increased level of vascular endothelial growth factor (VEGF) in testicular veins, the presence of VEGF mRNA and of its receptor, KDR, and an absence of detectable VEGF receptor Flt-1, in blood vessels of tumour marginal zones and of peri-tumour areas. This is in contrast to the capillaries within normal Leydig cell clusters which demonstrate both Flt-1 and KDR. Ultrastructural destabilisation of the vascular wall, evident as a lack of basement membrane and of peri-endothelial cells was also present in nearly 85% of blood vessels of the peri-tumour areas. In contrast, approximately 89% of the blood vessels of the tumour centre region demonstrated a stabilised vascular wall including basement membrane and peri-endothelial cells. Local application of VEGF(165) to the normal testicular tissue induced significant ultrastructural destabilisation in the capillary walls which only expressed KDR. These results suggest an autocrine role of VEGF on endothelial cells of tumour blood vessels in a region-specific manner and implicate that VEGF interactions with KDR, in the absence of Flt-1, may be involved in vascular destabilisation. In addition, the finding that most (79%) of Leydig tumour blood vessels are stabilised may account for the low malignant potential of these tumours.