Abstract Background Comprehensive sexuality education (CSE) is globally acknowledged as the most effective approach to promoting sexual health and preventing Sexually Transmitted Infections (STIs). However, in Italy, CSE is not consistently part of the school curriculum. The EduForIST project, funded by the Ministry of Health, introduced and tested a unique CSE model in a sample of secondary schools across six Italian regions, aiming to develop an evaluation model for potential nationwide implementation. Methods The EduForIST partnership, comprising experts from various institutions, devised a framework for monitoring and evaluating CSE interventions. Through monthly focus group discussions from April 2023 to February 2024, they established indicators for short-, medium-, and long-term evaluation of clinical and behavioral outcomes, as well as process indicators to assess intervention implementation. Results A total of 35 indicators were developed, including clinical and behavioral ones for medium and long-term outcomes, short-term behavioral outcomes, and process indicators. Data for clinical and behavioral indicators can be obtained from administrative sources like the Ministry of Health and Regional Health Authorities. The National Institute of Health provides data from relevant surveillance programs. However, many process indicators require specific data collection and calculations. Challenges such as under-reporting and underestimation persist, especially in regions with limited CSE implementation. Conclusions Creating an effective monitoring system for CSE interventions necessitates integrating diverse data sources, including health records, administrative data, and behavioral assessments. The proposed model’s effectiveness will be fully assessed by comparing pre- and post-intervention after widespread implementation in secondary schools. Meanwhile, the selected indicators serve as a foundation for evaluating baseline status of STIs and behaviors in Italy. Key messages • The EduForIST project establishes a robust framework for evaluating Comprehensive Sexuality Education (CSE) interventions in secondary schools, addressing gaps in nationwide implementation. • By devising indicators encompassing several measures, the project lays the groundwork for a comprehensive monitoring system, vital for assessing the effectiveness of CSE interventions in Italy.