This study examined the hypothesis that a brief, strengths-based home visiting strategy can promote positive engagement between caregiver and child and thereby reduce various forms of early childhood neglect. A total of 731 low-income families receiving services through the Women, Infants, and Children nutritional supplement program were randomized to the Women, Infants, and Children as usual or the Family Check-Up intervention. Assessments and intervention services were delivered in the home environment at ages 2, 3, 4, and 5. During the assessments, staff videotaped caregiver–child interactions and rated various features of the home environment, including the physical appropriateness of the home setting for children. Trained observers later coded the videotapes, unaware of the family's intervention condition. Specific caregiver–child interaction patterns were coded and macroratings were made of the caregiver's affection, monitoring, and involvement with the child. An intention to treat design revealed that randomization to the Family Check-Up increased duration of positive engagement between caregivers and children by age 3, which in turn was prognostic of less neglect of the child at age 4, controlling for family adversity. It was also found that family adversity moderated the impact of the intervention, such that the families with the most adverse circumstances were highly responsive to the intervention. Families with the highest levels of adversity exhibited the strongest mediation between positive engagement and reduction of neglect. Findings are discussed with respect to developmental theory and their potential implications for a public health approach to the prevention of early childhood maltreatment.