Background Australia's National Cervical Screening Program currently recommends cytological screening every 2 years for women aged 18–69 years. Human papillomavirus (HPV) vaccination was implemented in 2007 with high population coverage, and falls in high-grade lesions in young women have been reported extensively. This decline prompted a major review of the National Cervical Screening Program and new clinical management guidelines, for which we undertook this analysis. Methods We did effectiveness modelling and an economic assessment of potential new screening strategies, using a model of HPV transmission, vaccination, natural history, and cervical screening. First, we evaluated 132 screening strategies, including those based on cytology and primary HPV testing. Second, after a recommendation was made to adopt primary HPV screening with partial genotyping and direct referral to colposcopy of women positive for HPV16/18, we evaluated the final effect of HPV screening after incorporating new clinical guidelines for women positive for HPV. Both evaluations considered both unvaccinated and vaccinated cohorts. Findings Strategies entailing HPV testing every 5 years and either partial genotyping for HPV16/18 or cytological co-testing were the most effective. One of the most effective and cost-effective strategies comprised primary HPV screening with referral of women positive for oncogenic HPV16/18 direct to colposcopy, with reflex cytological triage for women with other oncogenic types and direct referral for those in this group with high-grade cytological findings. After incorporating detailed clinical guidelines recommendations, this strategy is predicted to reduce cervical cancer incidence and mortality by 31% and 36%, respectively, in unvaccinated cohorts, and by 24% and 29%, respectively, in cohorts offered vaccination. Furthermore, this strategy is predicted to reduce costs by up to 19% for unvaccinated cohorts and 26% for cohorts offered vaccination, compared with the current programme. Interpretation Primary HPV screening every 5 years with partial genotyping is predicted to be substantially more effective and potentially cost-saving compared with the current cytology-based screening programme undertaken every 2 years. These findings underpin the decision to transition to primary HPV screening with partial genotyping in the Australian National Cervical Screening Program, which will occur in May, 2017. Funding Department of Health, Australia.