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 ¼ 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 429 years). The global negative predictive value (NPV) of double-negative tests is thus of 99.9% (ninetyfive 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 449 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. It is now well established that oncogenic (high-risk) human papillomaviruses (HPV) are a necessary causal factor in the development of cervical intraepithelial and invasive neoplasias (Lorincz et al, 1992; Bosch et al, 1995;Walboomers et al, 1999;Zur Hausen, 2002). Infections with high-risk HPV (HR-HPV) are associated with a relative risk of between 8 and 11 for the development of squamous intraepithelial lesions (SIL) (Gaarenstroom et al, 1994). Moreover, only low-grade SIL (LSIL) containing HR-HPV progress to high-grade SIL (HSIL) (Koutsky et al, 1992). Owing to this, there is an increasing interest in using HPV DNA detection either alone or in addition to classic cytological examination for primary cervical screening (Cuzick et al, 1995(Cuzick et al, , 1999(Cuzick et al, , 2003Meijer et al, 1998;Clavel et al, 1999Clavel et al, , 2001Kuhn et al, 2000;Ratnam et al, 2000;Schiffman et al, 2000;Schneider et al 2000;Kjaer et al, 2002;Petry et al, 2003;Lorincz and Richart, 2003;Sherman et al, 2003). Most authors consider that a positive HPV testing selects a population at high risk for developing an HSIL, while a negative HPV testing has a very good negative predictive value (NPV). Indeed, considering that the mean time from detectable LSIL to preclinical invasive cancer is 12 -13 years (Gustafson and Adami, 1989), Meijer et al (1998) have proposed that women with cytologically normal smears and a negative HR-HPV test could be rescreened every 8 years.Hybrid Capture-II (HC-II), a commercial HPV detection test, (Digene, Gaithersburg, MD, USA) was introduced 7 years ago (Lorincz, 1996). Hybrid Capture-II is a nonradioactive, reproducible, relatively rapid, liquid hybridisation assay in microtiters designed to detect 18 HPV types divided into high-risk (types 16, 18, 31, 33, 35, 39, 45, 51, ...