Vascular endothelial growth factor (VEGF) is a key cytokine responsible for the spontaneous new blood vessel formation in the course of peripheral ischemia. It has repeatedly been observed in patients with critical leg ischemia that their clinical status does not reflect any effective local neovascularization processes as well as VEGF system up-regulation. Therefore, the aim of present study was to compare the proangiogenic status, assessed as the serum VEGF concentration, in patients with mild, moderate, and severe peripheral ischemia and to analyze to what extend it is influenced by the therapy applied. Serum VEGF level was evaluated by ELISA method in 31 patients with peripheral ischemia at different time points throughout the treatment. On Day 0 (before treatment), Day 2, and Day 7, VEGF concentration was significantly higher in subjects with critical leg ischemia (Group I) than in other groups (P<0.001). In Group I, VEGF decline was reported on Day 30 following radical surgery, while in a group of moderate disease treated by revascularization surgery a significant increase in serum VEGF concentration was observed (Day 7 and Day 30) (P=0.02). Serum cytokine level in the patients with mild ischemia (Group III) on pharmacotherapy was stable throughout the observation period. Interestingly, the increase in VEGF levels throughout the study period from Day 0 to Day 30 was significantly greater in unsuccessfully treated patients compared with subjects who positively responded to therapy or did not show any response at all. We conclude that mechanisms other than hypoxia might drive the observed up-regulation of VEGF production in peripheral ischemia.