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Introduction: The clinical course of high-grade cervical intraepithelial neoplasia (CIN2/3) is characterised by a high spontaneous regression rate. Histological assessment is unable to differentiate between CIN2/3 lesions likely to regress and those likely to persist or progress. Most CIN2/3 lesions are treated by surgical excision, leading to overtreatment of a substantial proportion. In this prospective study, we evaluate the value of DNA methylation of host cell genes, which has shown to be particularly sensitive for the detection of advanced CIN2/3 and cervical cancer, in the prediction of regression or non-regression of CIN2/3 lesions., Methods and Analysis: This is a multicentre observational longitudinal study with 24-month follow-up. Women referred for colposcopy with an abnormal cervical scrape, who have been diagnosed with CIN2/3 and a small cervical lesion (≤50% of cervix) will be asked to participate. Participants will be monitored by 6-monthly cytological and colposcopic examination. In case of clinical progression, participants will receive treatment and exit the study protocol. At baseline and during follow-up, self-sampled cervicovaginal brushes and cervical scrapes will be collected for high-risk human papillomavirus (HPV) testing and FAM19A4/miR124-2 methylation analysis. A colposcopy-directed biopsy will be taken from all participants at the last follow-up visit. The primary study endpoint is regression or non-regression at the end of the study based on the histological diagnosis. Regression is defined as CIN1 or less. Non-regression is defined as CIN2 or worse. The secondary study endpoint is defined as HPV clearance (double-negative HPV test at two consecutive time-points). The association between methylation status and regression probability will be evaluated by means of χ 2 testing., Ethics and Dissemination: Ethics approval was obtained in all participating clinics. Results of the main study will be submitted for publication in a peer-reviewed journal., Trial Registration Number: NTR6069; Pre-results., Competing Interests: Competing interests: DAMH and CJLMM are minority shareholders of Self-screen B.V., a spin-off company of VU University Medical Center; Self-screen B.V. holds patents related to the work (ie, high-risk HPV test and methylation markers for cervical screening); DAMH has been on the speakers bureau of Qiagen and serves occasionally on the scientific advisory boards of Pfizer and Bristol-Myers Squibb; JB received consultancy fees from Roche, GlaxoSmithKline and Merck, and received travel support from DDL. All fees were collected by his employer; CJLMM has received speakers fee from GSK, Qiagen, and SPMSD/Merck, and served occasionally on the scientific advisory board (expert meeting) of GSK, Qiagen, and SPMSD/Merck; CJLMM has a very small number of shares of Qiagen and holds minority stock in Self-screen B.V.; CJLMM is part-time director of Self-screen B.V. since September 2017., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)