Background: Postpartum depression is a devastating condition that affects a significant number of women and their offspring. Few preventive interventions have targeted high risk youth, such as American Indians (AIs). Objective: To evaluate the feasibility of a depression prevention program for AI adolescents and young adults. Methods: Expectant AI women (mean age = 18.15; N = 47) were randomized (1:1) to either the "Living in Harmony program" (LIH, an 8 lesson cognitive-behaviorally based program) or an Educational-Support program (ES, an 8 lesson education program). Both interventions were delivered by AI paraprofessionals. Adolescents were evaluated during their pregnancy at baseline, at post-intervention, and at 4, 12, and 24 weeks postpartum. The primary outcome measure was the Center for Epidemiological Studies-Depression scale (CES-D). Additional measures of depression included the onset of major depressive disorder (MDD; assessed via computerized diagnostic interview) and the Edinburgh Postpartum Depression Scale (EPDS). Secondary outcomes included changes in mothers' global functioning and social support. Results: At all post intervention assessments, mothers in both groups showed similar reductions in depressive symptoms and similar rates of MDD (0 and 6% in LIH and ES respectively). Both groups of participants also showed similar improvements in global functioning. No changes in either group were found on the measure of social support. Conclusions: Findings suggest that both paraprofessional-delivered interventions may reduce symptoms of depression among AIs. Replication with a larger sample, a usual care control condition, blinded evaluators, and a longer follow-up is needed.