Management of patients infected with high-risk HPV (hrHPV) despite normal colposcopy following abnormal cytology remains a clinical challenge. The aim of this study was to evaluate if, in that specific population, initial HPV 16 and HPV 18 viral loads are predictive of infection clearance over a 24-month follow-up. A total of 67 women infected with hrHPV having normal colposcopy following equivocal or low-grade cytological abnormalities were recruited and attended regular follow-ups based on repeat colposcopies and HPV testing. HPV16 and HPV18 infection were diagnosed in 36 (53.7%) and 7 (10.4%) cases, respectively. Viral load was quantified using the quantitative duplex real-time PCR method. Although this was not observed for HPV 18, initial HPV 16 viral load was highly associated to HPV 16 infection outcome (receiver operating characteristic curve analysis, area under curve: 0.90). Thus, women who had cleared their HPV 16 infection had significantly lower median initial HPV 16 viral load than those with persistent HPV 16 infection: 1.5 × 103 copies per million cells (CPMC) versus 3.8 × 106 CPMC, respectively (P = 0.006). The best prediction of HPV 16 clearance was obtained with an initial HPV 16 viral load of <7.5 × 104 CPMC: 86.7% specificity and 85.7% sensitivity. Finally, six patients were diagnosed with grade 2 or 3 cervical or vaginal intraepithelial neoplasia. Although all had a persistent hrHPV infection, neither HPV 16 nor 18 viral loads were found to be predictive of the risk of cervical or vaginal intraepithelial neoplasia. HPV16 viral load quantitation could represent a clinically useful marker in that very specific population. J. Med. Virol. 84:964–972, 2012. © 2012 Wiley Periodicals, Inc.