OBJECTIVES: Consensus US cervical cancer screening guidelines recommend use of co-testing (combination Pap plus HPV testing) for women aged 30-65 years. Though not currently recommended by US guidelines, an HPV test was approved by the FDA in 2014 for primary cervical cancer screening in women 25 years and older. In this study, we perform clinical-economic comparisons of co-testing with genotyping (Co-test GT) versus primary HPV with genotyping and reflex cytology (HPV GT) for cervical cancer screening. METHODS: A health state transition (Markov) model with one-year cycling was developed using epidemiologic, clinical, and economic data from healthcare databases and published literature. A cohort of one million women receiving triennial cervical cancer screening was simulated from ages 30-70 years. Screening strategies compared HPV GT to Co-test GT. Outcomes included total and incremental differences in costs, invasive cervical cancer (ICC) cases, ICC deaths, and quality-adjusted life years (QALYs) for cost-effectiveness calculations. Comprehensive sensitivity analyses were performed.  RESULTS: In a simulation cohort of one-million 30-year-old women modeled up to age 70, the model predicted as many as 2,141 ICC cases and 2,040 ICC deaths could be prevented with Co-test GT versus HPV GT. Co-test GT demonstrated a greater number of lifetime QALYs (22,334) and yielded $36.1 million in savings compared with HPV GT, thereby conferring greater effectiveness at lower cost. Applying this model to the cross-section of 78.9 million US women aged 30-70 years predicts nearly 150,000 ICC cases and more than 100,000 ICC deaths could be avoided with Co-test GT versus HPV GT, representing cost savings of approximately $4 billion over 40 years.  CONCLUSIONS: Model results demonstrate that co-testing with genotyping provides superior clinical and economic outcomes when compared to primary HPV testing with genotyping and reflex cytology. These findings are important to US healthcare payers and women’s health policy advocates seeking cost-effective cervical cancer screening technologies.