Rationale: Mesothelioma has become a major health burden since World War II because of the use of asbestos. Although many countries have imposed bans on asbestos, there remain significant mortality and morbidity from mesothelioma because of its long latent period and aggressiveness. Also, the use of asbestos is increasing in low-income countries, potentiating risk of mesothelioma in the coming decades. Assessment of the global burden of mesothelioma is required to take proper measures against the disease. Objectives: To assess the burden of mesothelioma from 1990 to 2019 at the global, regional, and national levels and to investigate patterns according to sex, age, sociodemographic index, and risk factors. Methods: The numbers, rates, and age-standardized rates of incidence, death, and disability-adjusted life years (DALYs) of mesothelioma in 204 countries and territories from 1990 to 2019 were estimated using vital registration and cancer registry data. The relationship between sociodemographic index and agestandardized DALY rate was determined, and DALYs attributable to occupational exposure to asbestos were calculated. Results: In 2019, there were 34,511 (95% uncertainty interval [UI], 31,199 to 37,771) incident cases of mesothelioma globally, with an age-standardized rate of 0.43 per 100,000 persons (95% UI, 0.38 to 0.47), which decreased between 1990 and 2019 by -12.6% (95% UI, -21.8% to -2.3%). Mesothelioma was responsible for 29,251 (95% UI, 26,668 to 31,006) deaths in 2019, with an age-standardized rate of 0.36 deaths per 100,000 persons (95% UI, 0.33 to 0.39), which decreased between 1990 and 2019 by -9.6% (95% UI, -17.8% to 21.1%). The age-standardized incidence rate increased in central Europe between 1990 and 2019 by 46.1% (95% UI, 16.6% to 72.4%). The Netherlands, Australia, and the United Kingdom had the highest agestandardized incidence rates. Incidence rates were higher in men than in women ages 45-49 to 90-94 years, peaking at 85-89 years. Occupational exposure to asbestos contributed to 85.2% (95% UI, 82.1% to 88.1%) of DALYs. Conclusions: The global burden of mesothelioma is decreasing in terms of age-standardized incidence and mortality rates. Mesothelioma remains a substantial public health challenge in many parts of the world.