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Summary: Background: Increasing premature mortality among some groups of Americans has been largely driven by increases in drug poisoning deaths. However, to our knowledge, a formal descriptive study by race and ethnicity, socioeconomic status, rurality, and geography has not been done. In this study, we examined US trends in premature all-cause and drug poisoning mortality between 2000 and 2015 at the county level among white, black, and Latino people. Methods: We used US mortality data for the period Jan 1, 2000, to Dec 31, 2015, including underlying cause of death and demographic data, collected from death certificates by the Centers for Disease Control and Prevention National Center for Health Statistics, and ascertained county attributes from the 2011–15 Census American Community Survey. We categorised counties into quintiles on the basis of the percentage of people unemployed, the percentage of people with a bachelor's degree, median income, and rurality. We estimated premature (ie, deaths in those aged 25–64 years) age-standardised mortality for all causes (by race and ethnicity) and drug poisoning, by county, for the periods of 2000–03 and 2012–15. We estimated annual percentage changes in mortality (2000–15) by county-level characteristics. Findings: Premature mortality declined from 2000–03 to 2012–15 among black and Latino people, but increased among white people in many US counties. Drug poisoning mortality increased in counties throughout the country. Significant increases between 2000 and 2015 occurred across low and high socioeconomic status and urban and rural counties among white people aged 25–64 years (annual percentage change range 4·56% per year [95% CI 3·56–5·57] to 11·51% per year [9·41–13·65]), black people aged 50–64 years (2·27% per year [0·42–4·16] to 9·46% per year [7·02–11·96]), Latino women aged 25–49 years (2·43% per year [1·18–3·71] to 5·01% per year [3·80–6·23]), and Latino men aged 50–64 years (2·42% per year [0·53–4·34] to 5·96% per year [3·86–8·11]). Although drug poisoning mortality increased rapidly in counties with the lowest socioeconomic status and in rural counties, most deaths during 2012–15 occurred in the largest metropolitan counties (121 395 [76%] in metropolitan counties with ≥250 000 people vs 2175 [1%] in the most rural counties), reflecting population size. Interpretation: Premature mortality has declined among black and Latino people in the USA, and increased among white people, particularly in less affluent and rural counties. Increasing drug poisoning mortality was not limited to poor white people in rural areas. Rapid increases have occurred in communities throughout the USA regardless of race and ethnicity, socioeconomic status, or rurality. Widespread public health interventions are needed to addess this public health emergency. Funding: National Institutes of Health.