Background: Postpartum depression (PPD) affects approximately 25% of women in lower-income and racial/ethnic minority populations in the USA. Evidence-based interventions for PPD screening and treatment exist, but many women with PPD are not identified or are inadequately treated. To address this gap, the American Academy of Pediatrics recommends screening for PPD at routine preventive visits in the first 6 months of postpartum, but less than half of pediatricians do so. Small PPD screening studies have been conducted in pediatric practices serving average-risk women, but less is known about practices serving families with lower-income and/or racial/ethnic minority status (safety-net practices). Study objectives were (1) to develop and pilot test an adaptable PPD screening protocol in safety-net practices and (2) to test strategies for implementing the protocol. Methods: The Consolidated Framework for Implementation Research was used for this two-phase pilot study. Phase I focus groups with pediatric providers and staff in four safety-net practices informed phase II development and implementation of a PPD screening and referral protocol. Feasibility measures included the percentage of eligible women screened and documentation of follow-up plans in the electronic health record at 1-, 2-, 4-, and 6-month preventive visits over 3 months. Implementation strategies were assessed for acceptability, appropriateness, and feasibility. Results: Focus group participants felt that (1) addressing PPD in the pediatric setting is important, (2) all clinical team members should be engaged in screening, (3) workflows and competing interests may present barriers, and (4) commonly used screening tools/approaches may not adequately detect depression in the population studied. During protocol implementation, screening rates increased from 75 to 85% for 324 eligible preventive visits and documentation of follow-up plans increased from 66 to 87%. Only 6.5% of women screened positive (EPDS > /= 10). Minor adaptations to implementation strategies were recommended to improve acceptability, appropriateness, and feasibility. Conclusions: Although developing and implementing an adaptable protocol for PPD screening in safety-net pediatric practices using external facilitation and a bundle of implementation strategies appear feasible, low positive screen rates suggest adaptations to account for intersecting patient, practice, and external policy contexts are needed to improve PPD screening effectiveness in these practices.