Recently, DNA methylation analysis of FAM19A4 in 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 of FAM19A4 methylation 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 for FAM19A4 gene 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, FAM19A4 methylation 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 of FAM19A4 methylation analysis were associated with age (p <= 0.001 each). In women >= 30 years (n=287), >= CIN3 sensitivity of FAM19A4 methylation 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 of FAM19A4 is an attractive marker for the identification of women with >= CIN3.