To compare the performance of human papillomavirus (HPV)-based screening to cytology-based screening in the real-world programme in China. A cross-sectional study. Tongzhou district, Beijing, China. Women aged 35-64 years old underwent both cytology and high-risk HPV genotyping testing. The study assessed the real-world performance of four common screening strategies, including cytology with HPV testing triage (Strategy 1), HPV testing with cytology triage (Strategy 2), HPV testing with HPV-16/18 genotyping and reflex cytology for other high-risk HPV types (Strategy 3), and co-testing with HPV genotyping testing and cytology (Strategy 4). Sensitivity, specificity, and colposcopy referral rate. The study included 50,933 eligible women. HPV prevalence was 7.0% (95% confidential interval [CI]: 6.8%-7.2%), and cytology abnormal rate was 3.5% (3.3%-3.6%). Strategy 4 had the highest sensitivity for CIN3+ (90.6%, 95%CI: 84.5%-94.5%), followed by Strategy 3 (84.8%, 77.5%-90.1%), which were significantly higher than Strategy 1 (65.0%, 56.3%-72.8%). Strategy 2 had the equivalent sensitivity (59.2%, 50.5%-67.4%) compared with Strategy 1. The specificities slightly differed within four screening strategies ranging from 97.3% to 98.7%. The colposcopy referral rates in Strategy 4 (2.3%) and Strategy 3 (2.0%) were significantly higher than that in Strategy 2 (1.3%) and Strategy 1 (1.4%). Co-testing or HPV testing incorporating HPV-16/18 genotyping provided higher sensitivity, similar specificity, and a slight increase of colposcopy referrals compared with cytology-based screening in a large-scale cervical cancer screening programme, supporting the utilization of HPV-based screening in the real world. National Natural Science Foundation of China (grant no 81903328). Cervical cancer screening, performance, HPV, cytology.