ImportanceLife expectancy is decreasing in the US. Without national efforts to address factors that support policies and programs directed at children living in areas of concentrated poverty, life expectancy will likely continue to decline while costs and suffering associated with unnatural deaths will increase.ObjectiveTo identify which childhood factors are associated with death from unnatural causes through midadulthood.Design, Setting, and ParticipantsFor this cohort study, longitudinal data on childhood characteristics came from a group-randomized intervention trial implemented in Baltimore City Public Schools, Baltimore, Maryland (baseline 1985-1986; all students entering first grade were selected to participate at age 6 years). Participants were followed up to midadulthood with a National Death Index search through December 31, 2020. Data analysis was performed from February to May 2023.ExposuresExposures included individual factors (ie, sociodemographic characteristics, teacher-reported aggressive behavior, self-reported depression, anxiety, early alcohol and cannabis use, and assaultive violence exposure), family and peer factors (ie, household structure and education level, deviant peer affiliation, and parental monitoring), and neighborhood factors (ie, rates of neighborhood assault and public assistance).Main Outcomes and MeasuresThe main outcome was unnatural death, defined as death due to unintentional injury, suicide, and homicide. A National Death Index search ascertained participants who died by age 41 to 42 years and cause of death. Multivariable Cox proportional hazards models were used to identify whether the exposures were independently associated with future mortality by unnatural causes.ResultsThe initial trial included 2311 children, and longitudinal data were available for 2180 participants (median [IQR] age in first grade, 6.3 [6.0-6.5] years; 1090 female [50.0%]; 1461 Black [67.0%]; 1168 received free or reduced lunch in first grade [53.6%]). A total of 111 male participants (10.2%) and 29 female participants (2.7%) died; among those who died, 96 male participants (86.5%) and 14 female participants (48.3%) died of unnatural causes. Two factors remained significantly associated with mortality from unnatural causes: female sex was associated with reduced risk (hazard ratio, 0.13; 95% CI, 0.08-0.22), and neighborhood public assistance was associated with increased risk (hazard ratio, 1.89; 95% CI, 1.09-3.30).Conclusions and RelevanceIn this urban population-based cohort study, no modifiable risk factors of mortality at the level of the individual (eg, depression or anxiety and substance use) or the family (eg, household education level) were identified. However, the degree of neighborhood poverty in early childhood was significantly associated with death by unnatural causes in early adulthood, suggesting that economic policies are needed to advance health equity in relation to premature mortality.