Importance: DNA methylation has been proposed as an epigenetic mechanism by which the childhood neighborhood environment may influence the genome to compromise adult health.Objective: To determine whether childhood neighborhood disadvantage is associated with differences in DNA methylation by age 18 years.Design: Longitudinal-prospective study of a 1994-95 birth cohort, followed to age 18 years (until September, 2014; 93% retention). Data analysis was performed from March to June 2019.Setting: United Kingdom. Participants: The nationally representative Environmental-Risk Longitudinal Study (N=2,232). Exposures: High-resolution neighborhood data (indexing deprivation, dilapidation, disconnection, and dangerousness) collected across childhood.Main Outcomes and Measures: DNA methylation in whole blood was drawn at age 18. Neighborhood-to-methylation associations were tested using three prespecified approaches: (1) testing probes annotated to candidate genes involved in biological responses to growing up in disadvantaged neighborhoods and investigated in previous epigenetic research (i.e., stress-reactivity and inflammation-related genes), (2) polyepigenetic scores indexing differential methylation in phenotypes associated with growing up in disadvantaged neighborhoods (i.e., obesity, inflammation, and smoking), and (3) a theory-free Epigenome-Wide Association Study (EWAS).Results: 1,619 participants (72.5% of cohort, 806[50%] female) had complete neighborhood and DNA methylation data. Children raised in disadvantaged neighborhoods exhibited differential DNA methylation in genes involved in inflammation (β=.12, 95%CI: .06, .19, p<.001) and exposure to tobacco-smoke (β=.18, 95%CI: .11, .25, p<.001) but not obesity (β=.05, 95%CI: -.01, .11, p=.123). EWAS identified multiple CpG sites at an array-wide significance level of p< 1.16x10−7 in genes involved in the metabolism of hydrocarbons. Neighborhood-to-methylation associations were small but robust to family-level socioeconomic factors and to individual-level tobacco smoking. Conclusions and Relevance: Children raised in disadvantaged neighborhoods enter young-adulthood epigenetically distinct from their more advantaged peers. This may be one mechanism by which the childhood neighborhood environment influences adult health.