ImportanceThe human papillomavirus (HPV) vaccine is safe and effective, yet vaccination coverage remains below public health objectives in many countries.ObjectiveTo examine the effectiveness of a 3-component intervention on HPV vaccination coverage among adolescents aged 11 to 14 years 2 months after the intervention ended, each component being applied alone or in combination.Design, Setting, and ParticipantsA cluster randomized trial with incomplete factorial design (PrevHPV) was conducted between July 1, 2021, and April 30, 2022, in French municipalities receiving 0, 1, 2, or 3 components of the intervention. Randomization was stratified by school district and municipalities’ socioeconomic level. Analyses were carried out on 11- to 14-year-old adolescents living in all participating municipalities, regardless of what had been implemented.InterventionThe PrevHPV intervention had 3 components: (1) educating and motivating 11- to 14-year-old adolescents in middle schools, along with their parents; (2) training general practitioners (GPs) on up-to-date HPV information and motivational interviewing techniques; and (3) free HPV vaccination at school.Main Outcomes and MeasuresThe primary outcome was HPV vaccination coverage (≥1 dose) 2 months after the intervention ended among 11- to 14-year-old adolescents living in participating municipalities, based on the French national reimbursement database and data collected during the trial in groups randomized to implement at-school vaccination.ResultsA total of 91 municipalities comprising 30 739 adolescents aged 11 to 14 years (15 876 boys and 14 863 girls) were included and analyzed. Half the municipalities were in the 2 lowest socioeconomic quintiles and access to GPs was poor in more than two-thirds of the municipalities. Thirty-eight of 61 schools (62.3%) implemented actions and 26 of 45 municipalities (57.8%) had at least 1 trained GP. The median vaccination coverage increased by 4.0 percentage points (IQR, 2.0-7.3 percentage points) to 14.2 percentage points (IQR, 9.1-17.3 percentage points) at 2 months. At-school vaccination significantly increased vaccination coverage (5.50 percentage points [95% CI, 3.13-7.88 percentage points]) while no effect was observed for adolescents’ education and motivation (−0.08 percentage points [95% CI, −2.54 to 2.39 percentage points]) and GPs’ training (−1.46 percentage points [95% CI, −3.44 to 0.53 percentage points]). Subgroup analyses found a significant interaction between at-school vaccination and access to GPs, with a higher effect when access was poor (8.62 percentage points [95% CI, 5.37-11.86 percentage points] vs 2.13 percentage points [95% CI, −1.25 to 5.50 percentage points]; P = .007 for interaction).Conclusions and RelevanceIn this cluster randomized trial, within the context of the late COVID-19 pandemic period and limited school and GP participation, at-school HPV vaccination significantly increased vaccination coverage. The trial did not show a significant effect for training GPs and education and motivation, although it may be observed after more time has elapsed after the intervention.Trial RegistrationClinicalTrials.gov Identifier: NCT04945655