OBJECTIVES: The objective of this HTA commissioned by the German Agency for Health Technology Assessment (DAHTA@DIMDI) and the Federal Ministry of Health was to systematically evaluate the long-term effectiveness and cost-effectiveness of HPV-based primary cervical cancer screening for the German health care context using a decision analytic approach. METHODS: A Markov model simulating the natural history of cervical cancer was developed and validated for the German health care context. Different screening strategies were evaluated, including cytology alone, HPV testing alone or combined with cytology or with cytological triage for HPV-positive women, and different screening intervals. German clinical, epidemiological and economic data were used. Test accuracy data were retrieved from international meta-analyses. Predicted outcomes were reduction in cervical cancer cases and deaths, life expectancy, and discounted incremental cost-effectiveness ratios (ICER). A perspective of the healthcare system and 3% annual discount rate were adopted. Extensive sensitivity analyses were performed to evaluate robustness of results. RESULTS: HPV-based screening was more effective than cytology alone, with 71%-97% (depending on screening intervals) relative reduction in cervical cancer compared to 53%-80% for cytology. The ICER ranged between €2,600/LYG (cytology, 5-yr-interval) and €155,500/LYG (annual HPV-testing age 30yrs, cytology 20-29yrs). Annual cytology, the current recommended screening strategy in Germany, was dominated by other strategies. Increasing screening start-age to 25yrs had no relevant loss in effectiveness but resulted in lower costs. CONCLUSIONS: Based on our analyses, HPV-based cervical cancer screening is more effective than cytology and could be cost-effective, when performed at intervals of two years or longer. For the German screening context, an optimal screening strategy could be biennial HPV testing starting at age 30yrs and biennial cytology at the age 25-29yrs. An extension to a 3-yearly screening interval may be considered for low-risk women with good screening adherence or in populations with low HPV incidence.