INTRODUCTION: Chronic wounds are defined as wounds that have not completed the reparative processes in a timely and adequate order in order to establish anatomical and functional integrity within 6 weeks. It is estimated that 1-2% of the population in developed countries suffers from a chronic wound. The highest percentage of chronic wounds occurs in diabetics. All chronic wounds are characterized by a prolonged and intensified pro-inflammatory cascade that does not allow the initiation of the proliferative phase of wound healing. Disturbed glycoregulation in diabetics leads to the development of endotheliopathy and neuropathy. As a consequence of these changes, foot ulceration occurs. The basic postulates of treating foot ulceration include stopping repeated tissue damage caused by postural mechanical pressure, debridement of the wound, control of infection and inflammation, adequate dressing and adequate regulation of glycemia. All measures are aimed at reducing the stimulation of immune cells and the production of pro-inflammatory cytokines, proteases and reactive oxygen radicals. The desired result is morphological and biochemical changes that will allow the chronic wound to progress from the inflammatory to the proliferative phase and thereby complete the healing process. OBJECTIVE: To determine the clinical and histomorphological changes in chronic diabetic foot ulceration after mechanical pressure relief therapy (off-loading therapy), with modified total contact cast, as well as to examine the correlation between the speed and extent of healing of chronic diabetic foot ulceration and changes in histomorphological parameters in relation to the use of modified total contact cast. MATERIALS AND METHODS: A prospective study included 80 patients, over 18 years of age, who suffer from diabetes with good glycoregulation (HbA1C ≤ 8%), and who have plantar neuropathic ulcer, without signs of infection and ischemia (ankle-brachial index , ABI ≥ 0.7) in the previous 8 weeks (SINBAD score ≤ 3). Patients were randomly divided into two groups (40 patients each). After the initial examination, the first group (TCC group) underwent off-loading treatment using total contact cast, which they wore for three weeks, after which the ulcer was biopsied. For this group of patients, after removing the total contact cast, the wound was bandaged twice a week, during the next 4 weeks. The second, control group (C group), had a biopsy of the ulcer taken after the initial examination. These subjects were bandaged twice a week, in the same way as the first group, for 4 weeks. In addition to the pathohistological analysis of the biopsy of the ulcer, the wound surface was measured before, during and after the treatment. RESULTS: 59 (73.7%) men and 21 (26.3%) women participated in the research, with an average age of 65.4 years. Most of the patients had no harmful habits (smoking, alcohol consumption). Most patients had type 2 diabetes mellitus (72; 92.5%), with no statistically significant difference between the TCC and C groups (Fisher’s exact test = 0.72; p = 0.68). The average ABI value for the TCC group was 0.90 ± 0.19, while for the C group it was 0.91 ± 0.14, with no statistically significant difference between the groups (U=755.50; p = 0.66) The classification of ulcer changes was performed according to the SINBAD classification system 33 (41.2%) of all subjects had grade 1, 15 (18.8%) grade 2 and 32 (40%) grade 3 subjects. It was not determined statistically significant difference between patients with total contact cast and patients from the control group with different SINBAD grades (χ2 test = 1.95; p = 0.38). The average duration of ulceration before the start of treatment was 5 months in the TCC group (the shortest was 1 month, the longest was 24 months), while in the C group it was 3 months (the shortest was 1 month, the longest was 19 months), with no statistically significant difference between the groups (U=637.00; p = 0.11). The average area of ulceration before the start of treatment in the TCC group was 2.46 ± 1.22 cm2, and in the C group 2.52 ± 1.14 cm2, with no statistically significant difference between the groups (U = 752.50; p = 0.6 5). A strong positive correlation was found between the duration and the area of ulceration before the start of treatment (r = 0.74; p < 0.001). Majority of the patients in the TCC group (23; 57.5%), had the ulceration less than 5 months with an average surface area of 0.56±0.14 cm2, while in 17 (42.5%) patients, in the same group, it lasted longer than 5 months with an average surface area of 1.87±0.33 cm2. A statistically significantly smaller surface area of ulceration was found in patients who had an ulcer lasting less than 5 months (U = 73.00; p = 0.001). In the TCC group, there was a decrease in the ulcer surface area, already after 3 weeks of wearing cast by an average of 28.23%, the average value of the surface area was 1.81 ± 1.13 cm2, and at the end of the treatment, the surface area of ulceration decreased by 61.87% in relation to the initial surface area, average values 1.12 ± 1.20 cm2. In the control group, at the end of the treatment, there was an increase in the average surface area of the wound by 13.05 ± 19.86% compared to the average initial surface area of chronic ulceration. In the TCC group, in 38 (95%) patients, pathohistological analysis verified the distribution of granulation tissue and neovascularization on more than 66% of the surface area of the examined biopsy sample. In the control group, the pathohistological analysis showed the highest distribution of inflammatory cells, cellular debris, hyperkeratosis and fibrosis in the majority of patients. A statistically significant association was found between the type of treatment and the final outcome after treatment (Fisher’s exact test = 61.59; p < 0.001). The correlation coefficient (Cramer’s V = 0.88; p < 0.001) indicates a strong positive correlation between these two variables. Of the total number of subjects with an improved chronic ulceration condition, as many as 36 (97.3%) patients belong to the group that wore total contact cast, while only 1 (2.7%) subject from the control group had an improved chronic ulceration condition. Without improved chronic ulceration, there were only 4 (9.3%) patients who wore total contact cast, while 39 (90.7%) subjects were from the control group. CONCLUSION: Treatment of chronic ulceration of the diabetic foot using total contact cast leads to mechanical relief from postural pressure on the tread surface, which triggers reparative processes in chronic ulceration with a consecutive faster reduction of the surface area and depth of the wound. The histomorphological changes of this therapy are characterized by a reduction of inflammatory cells, cellular and bacterial debris, fibrosis and hyperkeratosis in the ulcer, as well as an increase in neoangiogenesis and the formation of granulation tissue. An earlier start of off-loading therapy and a shorter duration of the ulcer have a favorable effect on the speed of wound healing. Mechanical debridement and regular dressing with an antiseptic solution lead to a more extensive and faster tissue repair of chronic ulceration in patients who underwent off-loading treatment, compared to the group of patients who were not relieved of mechanical pressure on the ulcer.