BACKGROUND: In France, human papillomavirus vaccine (HPVV) coverage among adolescents remains below the national objective. The PrevHPV randomised trial assessed three intervention components to improve HPVV coverage among adolescents: educational and motivational activities (EMM); vaccination campaigns (FA) in middle schools; and General Practitioner (GP) training. FA increased vaccine uptake, while EMM improved vaccine uptake or intention, as well as HPVV-related knowledge, attitudes, and practices (KAP). This secondary analysis aimed to assess whether the positive effect of EMM on HPVV uptake or intention was mediated by specific KAP improvements. METHODS: A total of 2758 adolescents aged 13 to 15 years from 39 schools completed online questionnaires at baseline and 5 months post-intervention. We created binary variables for the outcome "gain in vaccine uptake or intention during follow-up" and for favourable changes in individual KAP items. We used mediation analyses to evaluate indirect effects of individual KAP items on the association between EMM and uptake/intention, adjusting for FA and GP components and accounting for school-level clustering. RESULTS: EMM was associated with an increase in HPVV uptake or intention (OR:1.57, 95% CI: 1.02-2.41). The strongest significant mediation effects occurred via improved attitudes toward the vaccine's benefit-risk balance (indirect effect OR(IE):1.14), vaccine safety (OR(IE):1.12) and accessibility (OR(IE):1.11), as well as for having discussed HPV vaccination with friends (OR(IE):1.11) and for higher self-rated level of knowledge about the vaccine (OR(IE):1.10). CONCLUSION: These results help understanding the specific positive effects of co-constructed in-class educational activities and underpin the importance of improving vaccine-related attitudes - not only knowledge.