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Importance: The feasibility of implementing genome sequencing as an adjunct to traditional newborn screening (NBS) in newborns of different racial and ethnic groups is not well understood., Objective: To report interim results of acceptability, feasibility, and outcomes of an ongoing genomic NBS study in a diverse population in New York City within the context of the New York State Department of Health Newborn Screening Program., Design, Setting, and Participants: The Genomic Uniform-screening Against Rare Disease in All Newborns (GUARDIAN) study was a multisite, single-group, prospective, observational investigation of supplemental newborn genome screening with a planned enrollment of 100 000 participants. Parent-reported race and ethnicity were recorded at the time of recruitment. Results of the first 4000 newborns enrolled in 6 New York City hospitals between September 2022 and July 2023 are reported here as part of a prespecified interim analysis., Exposure: Sequencing of 156 early-onset genetic conditions with established interventions selected by the investigators were screened in all participants and 99 neurodevelopmental disorders associated with seizures were optional., Main Outcomes and Measures: The primary outcome was screen-positive rate. Additional outcomes included enrollment rate and successful completion of sequencing., Results: Over 11 months, 5555 families were approached and 4000 (72.0%) consented to participate. Enrolled participants reflected a diverse group by parent-reported race (American Indian or Alaska Native, 0.5%; Asian, 16.5%; Black, 25.1%; Native Hawaiian or Other Pacific Islander, 0.1%; White, 44.7%; 2 or more races, 13.0%) and ethnicity (Hispanic, 44.0%; not Hispanic, 56.0%). The majority of families consented to screening of both groups of conditions (both groups, 90.6%; disorders with established interventions only, 9.4%). Testing was successfully completed for 99.6% of cases. The screen-positive rate was 3.7%, including treatable conditions that are not currently included in NBS., Conclusions and Relevance: These interim findings demonstrate the feasibility of targeted interpretation of a predefined set of genes from genome sequencing in a population of different racial and ethnic groups. DNA sequencing offers an additional method to improve screening for conditions already included in NBS and to add those that cannot be readily screened because there is no biomarker currently detectable in dried blood spots. Additional studies are required to understand if these findings are generalizable to populations of different racial and ethnic groups and whether introduction of sequencing leads to changes in management and improved health outcomes., Trial Registration: ClinicalTrials.gov Identifier: NCT05990179.