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The Maternal, Infant, and Early Childhood Home Visiting Program was reauthorized February 8, 2018, and invests $2 billion over 5 years to improve mothers' and children's outcomes across the life course. Along with this investment, the home-visiting field is striving for implementation innovations to deliver the greatest impact to the most families at the most efficient cost through a focus on precision home visiting. Consistent with the precision home-visiting approach to identify meaningful subgroups to guide content tailoring, the purpose of this paper is to answer (1) how and to what degree an evidence-based home-visiting model benefits mothers and children with substance use or depression and (2) what baseline characteristics indicate who can benefit most. We completed a secondary data analysis of the most recently completed randomized controlled trial (RCT) of Family Spirit (N = 322), a federally endorsed home-visiting intervention designed for young Native American mothers and their children. We examined how baseline differences in mothers' substance use, depression, and demographic characteristics (household mobility, education, parity, and premature birth) moderated mothers' and children's intervention-related outcomes. Children born to mothers with past substance use histories benefited more from the intervention than children born to abstinent mothers (p &lt; 0.01). Unstable housing, parity, and low educational attainment emerged as moderators of intervention effectiveness. Results from this investigation will serve as a basis for designing and evaluating a precision approach to Family Spirit and may provide lessons for other models to explore tailoring variables for optimal impact and efficiency. Trial Registry: NCT00373750.

Informing Precision Home Visiting: Identifying Meaningful Subgroups of Families Who Benefit Most from Family Spirit