Engaging individuals in middle management positions (eg, nurse or clinic managers) could facilitate implementation of evidence-based interventions (EBIs) to improve uptake of human papillomavirus (HPV) vaccination. Our goal was to understand middle managers' role in and perspectives on implementation of EBIs for HPV vaccination. We conducted qualitative interviews with middle managers in pediatric and family practice clinics. We used constructs from the Consolidated Framework for Implementation Research (CFIR) to design the interview guide and as a coding framework. Participants (n = 19) reported overseeing implementation related to HPV vaccination. Across interviews, CFIR inner setting constructs (eg, structural characteristics and implementation climate) were identified as being both barriers and facilitators. As evidenced in this study, middle managers have a deep understanding of organizational factors, and they have the ability to facilitate implementation efforts related to HPV vaccination. Future efforts could focus on engaging middle managers and leveraging their expertise and understanding of barriers and facilitators.