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Recently, DNA methylation analysis ofFAM19A4in cervical scrapes has been shown to adequately detect high-grade cervical intraepithelial neoplasia and cervical cancer (≥CIN3) in high-risk HPV (hrHPV)-positive women. Here, we compared the clinical performance ofFAM19A4methylation analysis to cytology and HPV16/18 genotyping, separately and in combination, for ≥CIN3 detection in hrHPV-positive women participating in a prospective observational multi-center cohort study. The study population comprised hrHPV-positive women aged 18–66 years, visiting a gynecological outpatient clinic. From these women, cervical scrapes and colposcopy-directed biopsies (for histological confirmation) were obtained. Cervical scrapes were analyzed forFAM19A4gene promoter methylation, cytology and HPV16/18 genotyping. Methylation analysis was performed by quantitative methylation-specific PCR (qMSP). Sensitivities and specificities for ≥CIN3 were compared between tests. Stratified analyses were performed for variables that potentially influence marker performance. Of all 508 hrHPV-positive women, the sensitivities for ≥CIN3 of cytology,FAM19A4methylation analysis, and cytology combined with HPV16/18 genotyping were 85.6, 75.6 and 92.2%, respectively, with corresponding specificities of 49.8, 71.1 and 29.4%, respectively. Both sensitivity and specificity ofFAM19A4methylation analysis were associated with age (p≤ 0.001 each). In women ≥30 years (n= 287), ≥CIN3 sensitivity ofFAM19A4methylation analysis was 88.3% (95%CI: 80.2–96.5) which was noninferior to that of cytology [85.5% (95%CI: 76.0–94.0)], at a significantly higher specificity [62.1% (95%CI: 55.8–68.4) compared to 47.6% (95%CI: 41.1–54.1)]. In conclusion, among hrHPV-positive women from an outpatient population aged ≥30 years, methylation analysis ofFAM19A4is an attractive marker for the identification of women with ≥CIN3.High-risk human papillomavirus (hrHPV) infection is key to the development of cervical cancer. HrHPV DNA testing offers a very sensitive screening tool, but women who test positive require follow-up testing to avoid over-diagnosis and over-treatment. This article is the first to compare the clinical performance ofFAM19A4methylation analysis for cervical (pre)cancer detection to cytology and HPV16/18 genotyping in a prospective observational multi-center cohort study in a hrHPV-positive gynecological outpatient population. Performance of methylation analysis to detect high-grade disease is dependent on age. Among hrHPV-positive women aged ≥30 years, methylation analysis appears a valuable alternative to cytology and HPV16/18 genotyping.