The human papillomavirus (HPV) vaccine is an important tool for cancer prevention. However, vaccination rates in Alabama, a state with high rates of HPV-related cancers, remain below the national average. Our objective was to develop a comprehensive assessment of HPV vaccination in our state, with the goal to make recommendations for tailored multilevel interventions. A multimodal approach with quantitative and qualitative data was used to determine barriers and facilitators to HPV vaccination in Alabama. This included a survey of pediatric care providers and structured interviews with pediatricians, parents, nurses and community stakeholders. Two separate investigators evaluated the interview transcripts for major themes that occurred in 65% or more interviews. Major barriers included lack of knowledge, concerns about vaccine safety, and the link between the HPV vaccine and sexuality. Qualitative interviews further revealed barriers such as misinformation received from the internet and parental vaccine hesitancy. Opportunities for increasing vaccination include parental education, establishment of a reminder system, increasing access to HPV vaccine providers, and education for providers. Additional facilitators revealed through interviews included: trust in physicians, using the internet or social media to propagate positive messaging, physicians and clinical staff education, utilizing existing technology more effectively, highlighting nurses' roles as partners in HPV prevention, and the potential of schools as a venue for promotion of the vaccine. Our data are consistent with prior research showing major barriers to HPV vaccination. Several recommendations for optimizing HPV vaccination uptake in Alabama on the patient, provider and system level are given.