Background: CareHPV is a highly promising screening HPV assay that functions as a simplified and rapid point-of-care test, making it particularly well-suited for low-resource areas. It exhibits high sensitivity for detecting cervical precancerous lesions in cross-sectional study design. However, there is still limited evidence on the long-term protection of careHPV testing in the practical setting. Methods: A government-led cervical cancer screening program was implemented in Ordos City, China, specifically targeting female residents aged 35-64 years since 2016. CareHPV specimens were collected and visual inspection with acetic acid and Lugol iodine (VIA/VILI) was performed in the baseline screening. Women who were HPV-positive or VIA/VILI-suspected cancer at baseline were invited for a one-year follow-up screening. At the same time, those who were HPV-negative were scheduled for a 5-year rescreening. Women diagnosed with cervical intra-epithelial neoplasia grade 2 or worse (CIN2+) would be referred to clinical treatment as per the clinical guidelines. The current study includes participants who had valid baseline screening results and attended follow-ups with valid careHPV results conducted between January 2017 and December 2021, aiming to assess the long-term risk stratification for careHPV. Cumulative incidence rate (CIRs) and hazard ratio (HRs) for CIN2+ were calculated, using survival analysis. Results: Among the 179,306 women enrolled in the baseline screening between 2016 and 2020, 12.60 % tested positive for careHPV, with 657 cases of CIN2+ identified. The final analysis included 18,562 women in our study, of whom 58.54 % were careHPV-positive at baseline. The final analysis consisted of 17,905 women who underwent screening between 2016 and 2020 and attended follow-ups from 2017 to 2021, with valid HPV results, and 657 women who identified as CIN2+ at the baseline. The 5-year CIRs were 0.003 and 0.101 among women who tested negative and positive for baseline careHPV, respectively. The 5-year CIRs for developing CIN2+ during follow-ups were 0.009, 0.009, and 0.11 for the groups of women who transitioned from careHPV-negative to positive (831, 4.64 %), careHPV-positive to negative (6688, 37.35 %), and maintained a stable positive careHPV status (3535, 19.74 %), respectively. Conclusions: Our findings support the long-term safety and protection of careHPV testing in 5-year follow-ups of screening programs. CareHPV represents a viable option for regions with limited healthcare resources. (c) 2024 The Author(s). Published by Elsevier Ltd on behalf of King Saud Bin Abdulaziz University for Health Sciences. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/4.0/).