Background: Extant obesity efforts have had a limited impact among low-income underserved children, in part because existing programs are limited in terms of their short duration and low dosage, limited accessibility and sustainability; and failure to address barriers faced by diverse low-income families. Methods: This two-arm, parallel, randomized controlled trial (RCT) tests whether delivering obesity prevention, as part of an ongoing home visitation program (HVP), is an effective approach for primary (infants) and secondary (mothers) obesity prevention among low-income, underserved families. This RCT further examines the role of maternal and social factors as key mechanisms of transmission of infants’ obesity risk, and the real-life costs of delivering obesity prevention as part of HVPs. Specifically, 300 low-income mothers/infants (6mo at baseline) participating in the Healthy Families America home visitation program in Antelope Valley (CA) will be recruited and enrolled in the study. Home visitors serving families will be randomly assigned to deliver the standard HVP curriculum with or without obesity prevention as part of their weekly home visits for two years. Anthropometric, metabolic and behavioral assessments of mothers/infants will be conducted at enrollment and after 6 and 18 months of intervention. Discussion: This study addresses the need to develop interventions targeting at-risk infants before they become obese. The proposed research is timely as the Institute of Medicine, the United States Department of Agriculture, and the Department of Health and Human Services are revising their recommendations to address key factors influencing obesity risk in children from birth to 24 months of age.