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Objective triage strategies are required to prevent unnecessary referrals for colposcopy in population‐based screening programs using primary high‐risk human papillomavirus (hrHPV) testing. We have identified several DNA methylation markers with high sensitivity and specificity for detection of high‐grade cervical intraepithelial neoplasia or worse (CIN2+) in women referred for colposcopy. Our study assessed diagnostic potential of these methylation markers in a hrHPV‐positive screening cohort. All six markers ( JAM3 ,  EPB41L3 ,  C13orf18 ,  ANKRD18CP ,  ZSCAN1  and  SOX1 ) showed similar association across histology in the hrHPV‐positive cohort when compared to the Dutch cohort (each  p  > 0.15). Sensitivity for CIN2+ was higher using methylation panel  C13orf18/EPB41L3/JAM3  compared to the other 2 panels (80%  vs . 60% ( ANKRD18CP/C13orf18/JAM3 ) and 63% ( SOX1/ZSCAN1 ),  p  = 0.01). For CIN3+ all three methylation panels showed comparable sensitivity ranging from 68% (13/19) to 95% (18/19). Specificity of  SOX1/ZSCAN1  panel (84%, 167/200) was considerably higher compared to  ANKRD18CP/C13orf18/JAM3  (68%, 136/200,  p  = 2 × 10 −5 ) and  C13orf18/EPB41L3/JAM3  (66%, 132/200,  p  = 2 × 10 −7 ). High negative predictive value (NPV) (91–95% and 96–99%) was observed for CIN2+ and CIN3+, for all three methylation panels, while positive predictive value (PPV) varied from 25 to 40% for CIN2+ and 15–27% for CIN3+. Interestingly, 118/235 samples were negative for all six markers (including 106 controls (89.8%), 6 CIN1 (5.1%), 5 CIN2 (4.2%) and 1 CIN3 (0.8%)). Methylation results from both independent cohorts were comparable as well as high sensitivity for detection of cervical cancer and its high‐grade precursors in hrHPV‐positive population. Our study therefore validates these methylation marker panels as triage test either in hrHPV‐based or abnormal cytology‐based screening programs.

DNA methylation markers as a triage test for identification of cervical lesions in a high risk human papillomavirus positive screening cohort