© 2014, Springer International Publishing Switzerland. Methods: A Markov cohort model compared four strategies: (1) cytology with reflex HPV testing for atypical squamous cells of undetermined significance (ASC-US); (2) co-testing with cytology and HPV testing; (3) HPV with reflex to cytology; and (4) HPV with 16/18 genotyping and reflex cytology (ASC-US threshold). Screening began at age 30 and was performed triennially over 40 years. Screening sensitivity and specificity values for cervical intraepithelial neoplasia (CIN) 3 were obtained from the Addressing THE Need for Advanced HPV Diagnostics (ATHENA) trial. Outcomes for a 1-year follow-up scenario wherein persistent disease was detected were estimated. Screening and cancer treatment costs were calculated from a US payer’s perspective in 2013. Costs and quality-adjusted life-years (QALYs) were discounted at 3 % annually.Background: There is limited understanding of the health economic implications of cervical screening with human papillomavirus (HPV)-16/18 genotyping.Objective: The aim of this study was to evaluate the cost effectiveness of cervical cancer primary screening with a HPV-16/18 genotyping test which simultaneously detects 12 other high-risk HPV types.Results: Applying a US$50,000/QALY threshold, strategy (4) dominated strategies (2) and (3) by reducing costs and cancer incidence and improving QALYs, and was cost effective versus strategy (1). Accounting for persistent ≥CIN 3 at 1 year, strategy (4) was cost effective versus all other strategies. Detecting HPV-16/18 resulted in earlier diagnosis of clinically relevant ≥CIN 3 at initial screening and efficient use of follow-up resources. Outcomes were most influenced by strategy performance.Conclusions: Incorporating HPV-16/18 genotyping is cost effective and may improve detection of CIN, thereby preventing cervical cancer.