Randomized clinical trials, a large NCI-Kaiser Permanente real-world follow-up study involving over one million women, and the three US FDA registration trials clearly demonstrate that HPV primary screening for cervical cancer is safe and effective. Co-testing that combines both HPV testing and cytology offers minimal, if any, additional benefit over HPV primary testing and increases costs, requires follow-up of HPV-negative women with ASCUS and LSIL that can lead to unnecessary colposcopies/biopsies and retains the medico-legal risk of false-negative cytology results. A number of countries have adopted HPV primary screening for their national screening programs and in the United States HPV primary screening is now classified as the preferred screening approach for women >25 years by the 2020 American Cancer Society guidelines.