Aim. To analyse effects of sulodexide on endothelium-dependent vasodilation (EDVD) of brain vessels in animals with experimental diabetes mellitus. Materials and methods. The study was performed on 45 Wistar male rats (180-219 g b.w.) allocated to 3 equal groups. Group 1 served as control, group 2 included rats with DM given physiological saline, group 3 was comprised of animals with DM given sulodexide (30 LRU for 4 weeks). The endothelial dysfunction (ED) was simulated by inducing DM (single v/v injection of 50 mg/kg streptozotocin). A month later, the endothelium-dependent and independent vasodilation was tested by registration of circulation in brain vessels in the projection of the middle cerebral artery, determination of Pourcelot?s and Gosling?s indices before and after administration of 0.001 mg/kg acetylcholine (Acros organics, USA), 300 mg/kg L-arginine (Acros organics, USA), 0.007 mg/kg nitroglycerin (MTKh, Moscow), 10 mg/kg nitro-L-arginine (Acros organics, USA). Samples for immunohistochemical analysis were prepared using antibodies against e-NOS and endothelin-1 (Novocastra TM) as recommended by the manufacturer. STATISTICA/w7.0 program for Windows (StatSoft Inc., USA) was used for basic statistical analysis of the results of all experiments. Results. Administration of acetylcholine to DM rats caused a much greater (2.58-fold) decrease of EDVD than in control animals whereas endothelium-independent vasodilation remained unaltered (following nitroglycerin administration); Pourcelot?s and Gosling?s indices significantly increased. DM rats given sulodexide showed lower Pourcelot?s and Gosling?s indices than untreated animals. Thus, impaired expression of antibodies against e-NOS and enhanced expression of anti-endothelin-1 antibodies (specific markers of endothelial disturbance) suggest development of ED in DM and endothelium protection by sulodexide that increases the eNOS level and decreases the endothelin-1 level thereby improving EDVD. Conclusion. Administration of sulodexide to DM rats increases the eNOS level and decreases the endothelin-1 level thereby improving EDVD.