OBJECTIVES: To systematically evaluate the long-term effectiveness and cost-effectiveness of different cervical cancer primary screening strategies for the Austrian health care context. METHODS: A Markov-state-transition model was developed for the Austrian health care context and applied to evaluate different screening strategies that differ by primary screening test (including cytology, p16/Ki-67-dual stain, and HPV-testing alone or in combinations), screening interval, age, and specific follow-up algorithms for positive test results. We used Austrian clinical, epidemiological and economic data (year 2014), and test accuracy data from international meta-analyses and trials. We adopted a health care system perspective and discounted costs and effects at 5% annually. Predicted outcomes were relative reduction in cancer incidence and death, and incremental cost-effectiveness ratios (ICER; in Euro per life year gained [LYG]). Comprehensive sensitivity analyses were performed. RESULTS: Within the same screening interval, HPV-based primary screening strategies are more effective (relative reduction cancer death: 56%-79% for 5-2 yearly screening intervals) compared with cytology (42%-69%) or with p16/Ki-67 testing alone (50%-76%). Adopting risk-based follow-up algorithms including p16/Ki-67 triage for women with ASCUS or LSIL and colposcopy referral for women with HSIL or p16/Ki-67-positivity can improve efficiency. In the base-case analysis (31-43% screening adherence in women below 60 years of age), biennial HPV-testing (with cytology triage of HPV-positive women) at the age of 30 years and biennial cytology (with p16/Ki-67-triage of women with ASCUS/LSIL) at younger age was considered cost-effective with an ICER of 43,700 Euro/LYG. In sensitivity analyses results were sensitive to HPV-test cost, cytology test accuracy, screening adherence rate and annual discount rate. CONCLUSIONS: Based on our results, biennial primary HPV screening with cytology triage in women age 30 years and older and biennial cytology with p16/Ki-67-triage in younger women can be considered as a cost-effective screening option for the Austrian context.