Background Enteric fever is a major public health challenge in developing countries. We conducted a systematic analysis from the Global Burden of Diseases 2021 Study to provide updated estimates of enteric fever's burden. Methods We presented estimates for incident cases and deaths, age-standardized incidence and mortality rates, years of life lost (YLLs), and case-fatality rates spanning the study period of 2017-2021, stratified by region, country, sociodemographic index (SDI), and age group. Random-effects Poisson regression for longitudinal data was used to estimate the association between SDI and case-fatality rates, adjusting for antimicrobial resistance patterns. Findings In 2021, there were 9.3 million global cases of enteric fever (95% uncertainty interval: 7.3-11.9) and 107.5 thousand deaths (56.1-180.8). The age-standardized incidence rate decreased from 152/100,000 person-years (118-195) in 2017 to 128/100,000 person-years (100-163) in 2021, and the mortality rate decreased from 1.87/ 100,000 person-years (0.95-3.18) to 1.50/100,000 person-years (0.78-2.54). There were wide geographical differences, with South Asia contributing the most cases and deaths. Age-standardized incidence exceeded the threshold for " high burden" of enteric fever (100/100,000 person-years) in 23 countries in 2021. Children under fi ve accounted for 40% of deaths and 47% of YLLs, with incidence and mortality peaking during the second year. Case-fatality was highest in low SDI countries and showed a global trend toward reduction, except among children aged 1-4 years. After adjusting for the prevalence of multidrug resistance, fl uoroquinolone non- susceptibility, and third-generation cephalosporin resistance, a higher SDI was associated with a lower case-fatality rate, with a 1.1% (0.7-1.7) reduction for each percentage point increase in SDI. Interpretation Despite notable improvements, several countries still showed a high burden of enteric fever, which remains a significant global health concern, especially among children under fi ve. Although enhancing water and sanitation systems is crucial, the most significant reductions in the global disease burden are likely to be achieved through broader vaccine coverage. This includes the use of typhoid conjugate vaccines, which are effective in infants and young children and offer extended protection, along with improved data collection and surveillance to guide vaccine distribution efforts across high-incidence areas. Funding This work was partially supported by " Ricerca Corrente" funding from Italian Ministry of Health to IRCCS Humanitas Research Hospital. Copyright (c) 2024 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).