This study evaluates the clinical performance of high-risk human papillomavirus (HR-HPV) testing, liquid-based cytology (LBC), and HR-HPV and LBC co-testing for detecting cervical intraepithelial neoplasia (CIN) in premenopausal and postmenopausal women.A total of 6,085 premenopausal and 4,766 postmenopausal women were recruited for cervical cancer screening using LBC and HR-HPV testing. Following screening, colposcopy and biopsy for pathology were performed according to established protocols. We calculated the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the curve (AUC) for detecting CIN2/3 or worse (CIN2/3+).The sensitivity of LBC for detecting CIN2+ was 73.4% (95% CI=60.7%-83.3%) in premenopausal women and 58.8% (95% CI=44.2%-72.1%) in postmenopausal women. In contrast, significantly higher sensitivities were observed for HR-HPV testing and HR-HPV and LBC co-testing, both of which showed sensitivities of 96.9% (95% CI=88.2%-99.5%) in premenopausal women and 98.0% (95% CI=88.2%-99.9%) in postmenopausal women. While HR-HPV and LBC co-testing demonstrated superior specificity compared with HR-HPV testing alone [95.8% (95% CI=95.2%-96.3%) vs. 86.3% (95% CI=85.4%-87.1%) in premenopausal women; 93.7% (95% CI=92.9%-94.3%) vs. 80.6% (95% CI=79.5%-81.7%) in postmenopausal women], it also exhibited the highest PPV for CIN2+ prediction [19.6% (95% CI=15.4%-24.4%) in premenopausal women; 14.5% (95% CI=10.9%-18.6%) in postmenopausal women] compared with LBC or HR-HPV testing alone.HR-HPV and LBC co-testing demonstrates comparable high clinical accuracy for detecting CIN2+ in both premenopausal and postmenopausal women, with a preference for its use in postmenopausal screening.Copyright © 2025 The Author(s). Published by Wolters Kluwer Health, Inc.