BackgroundCervical cancer is the leading cause of cancer death in Zambia, where HIV prevalence is also high (11.3%). HIV heightens the risk of developing and dying from cervical cancer. The human papillomavirus (HPV) vaccine can prevent 90% of cervical cancers, and in Zambia is recommended for adolescent girls ages 14–15 years, including those with HIV. Currently they mainly deliver HPV vaccination via school-based campaigns, which may exclude the most vulnerable adolescents—those out-of-school or who irregularly attend. Adolescents living with HIV (ALHIV) are more likely to have these vulnerabilities. Further, school-based campaigns are not tailored to the WHO-recommended HPV vaccination schedule for ALHIV (3 versus 2 doses). Integrating HPV vaccination into routine care in adolescent HIV clinics may ensure that ALHIV have access to vaccine at the WHO-recommended schedule. Such integration requires a multilevel approach, stakeholder engagement, and diversified implementation strategies, given known challenges of providing the HPV vaccine in LMICs, including Zambia.MethodsOur study aims to integrate HPV vaccination into routine care in adolescent HIV clinics. To achieve success, we will co-design a package of implementation strategies using a previously successful implementation research approach developed for cervical cancer prevention in LMICs: the Integrative Systems Praxis for Implementation Research (INSPIRE). INSPIRE is a novel, comprehensive approach to develop, implement, and evaluate implementation science efforts. Following key elements of INSPIRE, our specific aims are to: 1) Identify the unique multilevel contextual factors (barriers and facilitators) across HIV settings (rural, urban, peri-urban) that influence HPV vaccine uptake; 2) Use Implementation Mapping to translate stakeholder feedback and findings from Aim 1 into a package of implementation strategies to integrate HPV vaccine into HIV clinics; 3) Conduct a Hybrid Type 3 effectiveness-implementation trial to evaluate the package of multilevel implementation strategies for integrating HPV vaccine into HIV clinics.DiscussionOur research team has strong support, technical expertise, and resources (e.g., vaccines) from the Zambian Ministry of Health; and political will for scale-up. This stakeholder-based implementation model has the potential to be transported to HIV clinics across Zambia and serve as a model to address cancer prevention priorities for those with HIV in other LMICs.Trial registrationTo be registered prior to Aim 3, when implementation strategies finalized.