BACKGROUND: This study aimed to assess the value of a HPV E6/E7 mRNA assay (Aptima® HPV [AHPV]) for primary cervical cancer screening combined with menopausal status. METHODS: A total of 16 917 women underwent AHPV testing and had complete histopathological results at the Affiliated Hospital of Jining Medical University China between January 1, 2017 and March 31, 2022. We evaluated the performance of different screening strategies and combined strategies, as well as evaluations of different menopausal states. RESULTS: When identifying LSIL+ (includes low- and high-grade squamous intraepithelial lesions and invasive cervical cancer [ICC]), the sensitivity (91.2%) and negative predictive value (NPV
96.6%) were significantly higher for AHPV than for liquid-based cytology assay (LBC
33.2% and 84.7% for sensitivity and NPV, respectively). Furthermore, the co-testing strategy (cytology combined with AHPV), when compared with AHPV, achieved a slightly higher sensitivity (93.6% vs. 91.2%, respectively, P <
0.001), a similar specificity (61.3% vs. 62.7%, respectively, P = 0.014), a similar positive predictive value (PPV
37.5% vs. 37.8%, respectively, P = 0.709) and a similar NPV (97.5% vs. 96.6%, respectively, P = 0.001). Moreover, AHPV (when compared with menopausal women) achieved a higher sensitivity (93.5% vs. 77.7%, respectively, P <
0.001), a higher NPV (97.3% vs. 93.9%, respectively, P <
0.001), a similar PPV (37.8% vs. 37.0%, respectively, P = 0.618) and a slightly lower specificity (60.7% vs. 72.1%, respectively, P <
0.001) in premenopausal women. These results were similar when identifying HSIL+ (includes high-grade squamous intraepithelial lesion and ICC). CONCLUSION: The present study suggests that initial screening with HPV E6/E7 mRNA testing rather than combined screening is a suitable candidate for cervical cancer screening in China (especially for premenopausal women) based on economic reasons.