Objective:To investigate the incidence of high-risk human papillomavirus (hrHPV) negative cervical lesions in the screening population, and based on this, to preliminarily evaluate the potential harm (missed diagnosis) and benefits (reduced colposcopy referral) of HPV primary screening compared to combined screening so as to provide reference for the selection of cervical cancer primary screening methods.Methods:This study was a single center cross-sectional study. Women who underwent joint screening [hrHPV typing test combined with cervical liquid based cytology test (LCT)] at the Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology from January 1, 2018 to December 31, 2019 were included in the cervical cancer screening. The proportion of hrHPV negative cytological abnormalities and cervical lesions in the population was analyzed and the theoretical colposcopy referral rate of the combined screening and HPV initial screening protocol was calculated. In the population with cervical pathological results, the number of colposcopy examinations required for the diagnosis of cervical intraepithelial neoplasia grade 2 and above (CIN2+ ) was calculated.Results:A total of 35 321 screened women were included. The overall incidence of hrHPV infection, LCT abnormalities and severe LCT abnormalities in the population was 17.13%(6 051/35 321), 18.07%(6 384/35 321), and 3.97%(1 402/35 321), respectively. The negative rate of hrHPV in women with severe cervical cytology abnormalities was as high as 51.28%(719/1 402), and in CIN2+ lesions diagnosed by cervical biopsy, hrHPV negative accounted for 7.15% (49/685). The theoretical colposcopy referral rates for combined screening and initial HPV screening were 11.28%(3 985/35 321) and 8.33%(2 943/35 321), respectively, with an average diagnosis of CIN2+ requiring 3.51 and 2.81 colposcopy examinations, respectively.Conclusions:In the opportunistic screening population, the proportion of hrHPV negative CIN2+ lesions cannot be ignored, and the HPV initial screening strategy may cause missed diagnosis of these lesions. However, compared to combined screening, HPV initial screening has the potential to improve the efficiency of colposcopy. These results suggest that we should carefully choose the HPV initial screening plan.