BACKGROUND: Human papillomavirus is a prevalent DNA virus and the leading cause of both oropharyngeal and cervical cancer. Despite the availability of an effective vaccine (HPV-V), uptake is below national targets. A behavioral intervention, Increasing HPV Vaccine Uptake - Delivered in Dental Settings (HPV-V Uptake-DDS), was developed to support dental providers in promoting HPV-V to their patients to help close this gap. OBJECTIVES: This protocol for an efficacy trial of HPV-V Uptake-DDS is designed to increase HPV-V promotion by dental practitioners, and subsequent vaccine uptake among adolescent and young adult patients. METHODS: The trial will be conducted in dental clinics in a single midwestern health system utilizing a prospective, two-arm, parallel, cluster-randomized controlled design. Eighteen clinics will be randomly assigned to either the intervention or usual care. The intervention includes didactic training, clinical decision support tool embedded in the electronic dental record, tip sheet, patient education handout, and practitioner performance reports. The primary outcome is change in HPV-V promotion by practitioners. Secondary outcomes include change in HPV-V uptake by patients and changes in three behavioral mechanisms: practitioner knowledge, self-efficacy, and fear of negative consequences related to HPV-V promotion. Outcomes will be captured from the electronic health record, practitioner surveys, patient or guardian surveys, and state vaccination registries. CONCLUSIONS: The protocol for a clinical trial will test the efficacy of the intervention and the measurement of behavioral mechanisms of action will inform which components of the intervention of needed to address barriers in different practice settings.