Background HPV vaccine coverage (VC) remains lower than expected in many countries, particularly France. We developed and evaluated the PrevHPV multicomponent intervention to improve HPV VC among French adolescents. We evaluated the implementation of the school-based components of the intervention. Methods We carried out a mixed-method study embedded in a cluster randomized controlled trial (July 2021-April 2022; 14/25 French school districts). The cluster was the municipality (n = 91). The school-based components of the intervention were ‘education and motivation’ and ‘at-school vaccination’. Quantitative data were collected through standardized activity reports and self-administered questionnaires; the implementation outcomes were fidelity, dose, reach, acceptability and sustainability. Qualitative data were collected through semistructured group interviews with school staff and analyzed using the Consolidated Framework for Implementation Research. Results We found high rates for: fidelity (e.g., 69% of the targeted classes had two educational sessions and 89% of schools invited all pupils for at-school vaccination, as planned); acceptability (e.g., pupils’ participation satisfying in 90% of the sessions, 96% of vaccinated pupils and 78% of school staff satisfied with at-school vaccination); and sustainability (e.g., respectively 91% and 76% of schools considered conducting sessions and vaccination days during the following year). However, the withdrawal of 1/3 of schools before the trial started and difficulties in mobilizing parents negatively impacted dose and reach. Several facilitators and barriers influenced the implementation of the components; they were related to the components’ design, the characteristics of both the external and internal environment of the school, the numerous stakeholders and individuals involved, and the implementation strategies used. Conclusions These results can guide policy making on school-based HPV vaccine promotion in France and Europe. Key messages • The PrevHPV study is supported by the French health authorities and conducted by a multidisciplinary consortium to tackle a long-lasting public health concern in France. • These findings have practical implications for implementing effective and acceptable school-based interventions in real life to improve HPV vaccine uptake and reduce HPV-associated burdens.