Objective: The detection and treatment of high-grade cervical lesions prevent the development of invasive cervical cancer. Excisional procedures can pose a risk for subsequent pregnancies, thus conservative management of Cervical Intraepithelial Neoplasia grade 2 (CIN2) lesions should be adopted in young women. The aim of our study is to evaluate the ability of viral and cellular biomarkers in predicting regression/progression of CIN2. Methods: Women aged 25 to 45 years, participating to population-based organised cervical cancer screening programmes in the Veneto Region (Italy), diagnosed with a CIN2 lesion and fitting predefined inclusion/exclusion criteria, are invited to take part in a multicentre observational longitudinal cohort study with a follow-up of 24 months. Upon signing an informed consent, women are enrolled in the study and cervical cell samples collected. Treatment is delayed and subsequently performed in the case of lesion progression, or persistence for >12 months. HPV genotyping, p16{}^{\text{INK4A}}/ki67 expression and methylation status for L1 viral sequences and FAM19A4/miR124-2 cellular genes are determined at baseline and during follow-up, and evaluated in relation to the clinical outcome. Results: The study, registered on ClinicalTrials.gov (ID: NCT04687267), is currently ongoing. Enrolment of women aged 25–45 years started in 2019, and will continue up to the end of 2021. Discussion: Since February 2020, the Veneto Region has been hit by the COVID-19 pandemic. The enrolment of women in the study was interrupted during an initial two-month lockdown, and slowed down during the subsequent months. The 12-month extension of the study period will partially counterbalance this delay.