Introduction: Chronic venous disease (CVD) is a disabling condition affecting about 1% to 3% of the general population. Besides varicose veins, CVD can result also in the formation of severe skin lesions, especially venous ulcerations (VU). The exact mechanism of VU is still unknown. Aim: To evaluate immunoexpression of vascular endothelial growth factor (VEGF) and cathepsin K in healthy individuals and patients with VU. Material and methods: The study included 12 patients with venous ulcers and 10 healthy individuals who served as controls; both groups were sex-and age-matched. Biopsy samples were obtained from lower leg areas and submitted to histochemical analysis. Results: There was a significant difference between the study group and the control group in cathepsin K expression (1.007 ±0.3 vs. 0.22 ±0.2, respectively, p < 0.001) and VEGF expression (1.17 ±0.59 vs. 0.27 ±0.19, respectively, p < 0.001). Additionally, the microvessel density (per mm 2 ) differed significantly between the study group and the control group (97.6 ±28.81 vs. 59.32 ±12.71, respectively, p < 0.001). We found no correlation between cathepsin K and microvessel density, and cathepsin K and VEGF in both groups, but there was a significant correlation between microvessel density and VEGF immunoexpression in the study group (r = 0.82, p = 0.002). Conclusions: Increased immunoexpression of VEGF and cathepsin K suggests that both of these proteins may play a role in VU development.