High-risk human papillomaviruses (HR-HPV) are the necessary cause of cervical carcinomas and there is an increasing interest in using HR-HPV DNA detection in adjunction to cytological examination for primary cervical screening. To determine whether women with a normal smear negative for HR-HPV DNA detection with the Hybrid Capture II assay might represent a low-risk population for developing a high-grade squamous intraepithelial lesion (HSIL), 4401 women have been followed in a period of 12-72 months (median=34 months). During this follow-up, four HSIL and one microinvasive carcinoma have been detected in this cohort (three in the cohort of 3526 women >29 years). The global negative predictive value (NPV) of double-negative tests is thus of 99.9% (ninety-five percent confidence interval (95% CI): 99.8-100%), whereas cytology alone gives an NPV of 99.2% (95% CI: 98.9-99.5%). If we obtain a second negative HR-HPV test 1-2 years after the initial test, the NPV is 100%. The NPV is also of 100% in the cohort of women >49 years. We conclude that all these women could be safely screened at longer intervals between 3 and 5 years. This policy will offset the increased costs induced by an additional HR-HPV testing in primary screening.