Introduction: Along with the mortality rate, the indicator of Potential Years of Life Lost (PYLL) is used to assess health losses in the population. Objective: To assess the structure and rates of mortality from diseases of the circulatory system and to estimate the number of potential years of life lost due to this category of disorders in the population of the Orenburg Region. Methods: We conducted a retrospective analysis of deaths registered among the population of the Orenburg Region in 2010– 2020 using a depersonalized database of medical death certificates within the mortality monitoring system of the Medical Information and Analytical Center of the Orenburg Region. The results were evaluated using parametric and nonparametric methods. Potential years of life lost due to the diseases of the circulatory system were estimated by 5-year age groups for the population aged 18–75 in the years 2019 and 2020. Results: We established that the greatest demographic and socio-economic damage was caused by the diseases of the circulatory system, external causes of death, and neoplasms. We also estimated that in 2019, the mortality rate from diseases of the circulatory system was 633.7 per 100,000 population, i.e. 0.7 % lower than that in 2018 (638.2 per 100,000). In 2010–2020, the circulatory disease mortality rate was the highest in 2010 (842.0 per 100,000 population) and the lowest in 2016 (608.2 per 100,000). The average age of the deceased was 72.9 ± 13.8 years, and we observed its increase from 72.0 ± 10.9 years in 2019 to 73.6 ± 9.4 years in the year 2020 (p = 0.014). In 2019, the indicator of premature mortality was 30,895 and 10,515 years for men and women, including 24,323 and 5,404 potential years of life lost in working-age men and women (< 59 and < 54 years of age), respectively. In 2020, the number of PYLL rose to 39,425 and 16,868 years in men and women, respectively. We found significant age and sex differences in the level of losses from premature mortality. Conclusion: Our findings show that the regional mortality rates from diseases of the circulatory system in 2010–2020 exceeded the national averages. The structure of causes of death from diseases of the circulatory system did not change. In 2020, the number of potential years of life lost increased compared to 2019 and was more than twice as high for men than for women.