The ongoing TRACE prospective, multicenter study aimed to provide a clinical evaluation of the CONFIDENCE assay, which comprises an HPV DNA and a human epigenetic biomarker test. Between 2013 and 2015 over 6,000 women aged 18 or older were recruited in Hungary. Liquid based cytology, hrHPV DNA detection and single target host-gene methylation test of the promoter sequence of the POU4F3 gene by quantitative methylation specific PCR were performed from the same LBC sample. The current analysis is focused on the baseline cross-sectional clinical results of 5,384 LBC samples collected from subjects aged 25 years or older. The performance of the CONFIDENCE HPV test was found to be comparable to the cobas(R) HPV test with good agreement. Applying the CONFIDENCE Marker test alone in hrHPV positives, it showed significantly higher sensitivity with matching specificity compared to LBC based triage. For CIN3+ histological endpoint in the age group of 25-65 and 30-65, the methylation test of POU4F3 achieved relative sensitivities of 1.74 (95% CI: 1.25-2.33) and 1.64 (95% CI: 1.08-2.27), respectively after verification bias adjustment. On the basis of our findings, POU4F3 methylation as a triage test of hrHPV positives appears to be a noteworthy method. We can reasonably assume that its quantitative nature offers the potential for a more objective and discriminative risk assessment tool in the prevention and diagnostics of high-grade CIN lesions and cervical cancer. This article is protected by copyright. All rights reserved.