This study tested the effectiveness of Promoting First Relationships® (PFR), a preventive intervention program aimed at fostering positive caregiver-child relationships in Native families living on a rural reservation. Participants were 162 primary caregivers (96% Native; 93% female) and their Native toddlers (10-31 months old; 50% female). Families were randomized to a PFR group (n = 81) or Resource and Referral (RR) control group (n = 81), after baseline data collection (Time 1) to assess the quality of caregiver-child interaction, caregiver knowledge about children's social-emotional needs, caregiver depressive symptoms, and child externalizing behavior. After delivery of the PFR intervention or the RR service, follow-up assessments were repeated immediately post-intervention (Time 2) and 3 months later (Time 3). After controlling for baseline assessments, multivariate analyses of covariance revealed that caregivers in the PFR group had significantly higher scores on knowledge about children's social-emotional needs at Time 2 (p < 0.01, [eta][superscript 2] = 0.06) and Time 3 (p < 0.05, [eta][superscript 2] = 0.04) and less severe depressive symptoms at Times 2 and 3 (both p < 0.05, [eta][superscript 2] = 0.04). At Time 3, the quality of caregiver-child interaction was better in the PFR group (p < 0.01, [eta][superscript 2] = 0.06), an effect that was moderated by severity of depressive symptoms (p = 0.05, [eta][superscript 2] = 0.06), with PFR having the greatest impact at low levels of initial symptoms (p = 0.02). Results support the positive impact of PFR in a Native community and suggest conditions under which the intervention may be most effective.