Abstract We studied the health and economic effects of human papillomavirus (HPV) DNA testing in cervical screening using a simulation model. The key data source was a Dutch longitudinal screening trial. We compared cytological testing with repeat cytology (for borderline/mildly abnormal smears) to HPV testing with cytology triage (for HPV‐positive smears), combination testing (combined HPV and cytology) and cytological testing with HPV triage (for borderline/mildly abnormal smears). We varied the screening interval from 5 to 10 years. The main outcome measures were the number of cervical cancer cases, the number of quality‐adjusted life years (QALYs), and the incremental cost‐effectiveness ratio (ICER). The base‐case estimates were accompanied with ranges across 118 calibrated parameter settings (calibration criteria: cervical intraepithelial neoplasia 2/3, cancer and mortality rates). In comparison to 5‐yearly cytology, 5‐yearly HPV testing with cytology triage gave a reduction in the number of cancer cases of 23% (range, 9–27%). The reduction was 26% (range, 10–29%) for combination testing and 3% (range, −1 to 8%) for cytology with HPV triage. For strategies with primary HPV testing, the model also estimated a reduction in cancer cases when the screening interval was extended to 7.5 years. Five‐yearly cytology with HPV triage and 5 to 7.5‐yearly HPV testing with cytology triage were cost effective for the base‐case settings and the majority of calibrated parameter settings (ICER below Dutch willingness‐to‐pay threshold of €20,000/QALY). Our model indicates that HPV testing with cytology triage is likely to be cost effective. An extension of the screening interval may be considered to control costs.