Introduction: Dipeptidyl-peptidase IV or molecule CD26 (DPP IV/CD26) is a ubiquitous transmembrane protein and a serine protease that cleaves numerous biologically active substrates, including those with important role in regulating blood glucose concentrations. Previous studies have indicated the important role of DPP IV/CD26 in angiogenesis, cell migration and apoptosis. However, the pathophysiological processes of wound healing in diabetes, which represent a significant public health problem, are not sufficiently clarified. The hypothesis of this research is a significant role of DPP IV/CD26 in the process of wound healing under experimental hyperglycemia conditions. The aim of this study was to establish an experimental model of diabetes and an experimental model of wound healing in CD26 deficient (CD26-/-) and wild type mice (C57BL/6), and to determine whether the DPP IV/CD26 deficiency influences on important neovascularization factors (VEGF and HIF-1α) by monitoring macroscopic and/or microscopic changes during the process of tissue regeneration and reparation under experimental hyperglycemia conditions. Materials and methods: The experimental model of diabetes was induced in CD26-/- and C57BL/6 mice by intraperitoneal administration of a streptozotocine solution in a citrate buffer at a dose of 50 mg/kg for 5 days. The development of diabetes was confirmed on the basis of clinical, biochemical and histological parameters. Then, experimental wounds were induced on the dorsal part of experimental animals, and animals were sacrified on the second, fourth, seventh, tenth and fifteenth days of wound healing. Histomorphometric, histopathological and immunochemical analysis of wound, control skin tissue and pancreas were preformed. The expression of neovascularization factors of VEGF and HIF-1α, the degree of corium regeneration and the degree of neovascularization of the corium during cutaneous wound healing was determined. The enzymatic activity of tissue DPP IV/CD26 in wild type animals during the wound healing process in experimental conditions of hyperglycemia was measured using a spectrophotometric method. Results: Obtained results confirmed a better tolerance of glucose in CD26-/- mice compared to the wild type. Histomorphometric analysis of wound tissue confirmed a higher degree of cortex regeneration and decreased duration of the inflammatory phase in CD26-/- mice, while C57BL/6 mice show slower formation of new epidermis and wound coverage. Furthermore, DPP IV/CD26 deficiency positively affects the formation of connective tissue as well as tissue. Expression of neovascularization factors HIF-1α and VEGF were statistically significantly higher (p<0.05) in CD26-/- animals compared to C57BL/6 mice in all examined days of tissue healing. The number of new capillaries in the cortex was statistically significantly higher (p<0.05) on the seventh and tenth day in the CD26-/- mice compared to C57BL/6 animals. The enzymatic activity of DPP IV/CD26 in wound tissue in conditions of experimental hyperglycemia, was statistically significantly lower (p<0.05) in C57BL/6 mice on the second, fourth and seventh day of healing compared to physiological values. Conclusion: The hypothesis of a significant role of DPP IV/CD26 in glucose homeostasis and in the process of tissue and reparation in conditions of experimental hyperglycemia has been confirmed. CD26 deficiency is associated with an improved glucose tolerance, a lower inflammatory response, increased expression of HIF-1α and VEGF neovascularization factors, and enhanced neovascularization of the cortex in healing wounds. Obtained results indicate the significance of DPP IV/CD26 inhibition as a possible therapy in the treatment of wound healing disorders in diabetic patients.