Adding a test for high-risk human papillomavirus (hrHPV) to cytological screening enhances the detection of high-grade cervical intraepithelial neoplasia (≥CIN2), but data are required that enable long-term evaluation of screening. We investigated the ≥CIN2 risk for women participating in population-based screening as a function of hrHPV and cytology testing results at baseline and at 6 months. We included 2,193 women aged 30–60 years participating in a population-based screening trial who received colposcopy or a repeat testing advice at baseline. The main endpoint was histologically confirmed ≥CIN2 diagnosed within 36 months. hrHPV testing was more sensitive than cytology for ≥CIN2 (relative sensitivity 1.4, 95%CI: 1.3–1.5; absolute sensitivity 94.1 and 68.0%, respectively). The 18-month ≥CIN2 risks in women with a hrHPV-positive smear and in women with abnormal cytology were similar (relative risk 0.9, 95%CI: 0.8–1.1). Women with HPV16 and/or HPV18 had a higher ≥CIN2 risk than other hrHPV-positive women irrespective of the cytological grade. Repeat testing showed that both cytological regression and viral clearance were strongly associated with a decrease in ≥CIN2 risk. Notably, women who had a double negative repeat test at 6 months had a ≥CIN2 risk of only 0.2% (95%CI: 0.0–1.1) and hrHPV-negative women with baseline borderline or mild dyskaryosis and normal cytology at 6 months had a ≥CIN2 risk of 0% (95%CI: 0.0–0.8). Using hrHPV and/or cytology testing, risk of ≥CIN2 can be assessed more accurately by repeat testing than single visit testing. Hence, when hrHPV testing is implemented, patient management with repeat testing is a promising strategy to control the number of referrals for colposcopy. © 2007 Wiley-Liss, Inc.