The aim of the study was to determine the pathogenetic role of endothelin-1 (ET1) and the connection of the rs6842241 polymorphisms of the EDNRA gene and rs5351 of the EDNRB gene with diabetes mellitus type 2 (DM2T) and its complications in the cohort of Ukrainian patients. Surveyed 152 patients aged 53.9±8.4 years and 95 people in the control group. Genetic polymorphisms were determined by real-time polymerase chain reaction (TaqMan Mutation Detection Assays Life-Technology; USA). The presence of an association of elevated blood levels of ET1 (3.7-4.7 times) and NO (1.4-1.5 times) with disease progression has been shown. The increase in ET1 level was associated with the development of retinopathy, nephropathy, determined by microalbuminuria and glomerular filtration rate, sensory polyneuropathy and arterial hypertension, and NO – with arterial hypertension and lower limb macroangiopathy. Endothelin receptor gene polymorphisms were associated with the development of DM2T: for rs6842241, an increased risk was associated with a minor allele A (odds ratio 1.87; 95% confidence interval 1.20-2.92; P=0.005), for rs5351 with ancestral allele C (odds ratio 1.54; 95% confidence interval 1.05-2.25; P=0.026). The presence of these alleles was associated with a higher blood level of ET1. Risk A allele rs6842241 contributed to higher body mass index, systolic and diastolic pressure and triglyceride level in blood compared to allele C. Carriers of rs5351 risk allele C were ill for three years longer, they had higher blood levels of urea and creatinine, microalbuminuria, as well as a lower glomerular filtration rate than T allele carriers. Thus, directly influencing the clinical and laboratory parameters and the development of complications, the rs6842241 and rs5351 endothelin receptor genes reduced the severity of DM2T.