High-risk papillomavirus (HR-HPV) testing combined with cytology improves the detection of cervical lesions and increases length of screening intervals. For a population-based HR-HPV survey, testing automation is in great need. The Cobas 4800 HPV Test System is a fully automated assay that can simultaneously detect HPV16, HPV18, and other 12 pooled HR-HPV genotypes. This system has been employed for HR-HPV screening in a number of countries; however, such application in a large population in China has not been documented. In this study, we employed the Cobas 4800 HPV Test System to detect HR-HPV in cervical cytology specimens collected from a total of 5650 asymptomatic women from a region of South China. We reported the following: (1) the prevalence of the 14 genotypes of HR-HPV was 12.96%; (2) for those with HR-HPV infection, 2.25% were positive for HPV16, 0.50% for HPV18, 9.15% for pooled 12 HPV types, and 1.06% for multiple HPV infection; and (3) there was no significant difference in the HR-HPV prevalence among different age groups. HPV16 and HPV18 have been shown to be the predominant HPV types found in cervical cancer patients in some regions in China, indicating that a fully automated assay like the Cobas 4800 HPV Test System is especially valuable for population-based HR-HPV screening in these regions as this assay can concurrently detect HPV16 and HPV18. Copyright © 2020 Shanyun Wang et al.