Background/Objective: Women treated with large loop excision of the transformation zone (LLETZ) for cervical intraepithelial neoplasia 2-3 (CIN2+) remain at CIN2+ risk for many years. We assessed the role of high-risk human papillomavirus (HR-HPV), surgical margins, and LLETZ characteristics in long-term risk of CIN2+. Methods: A retrospective observational study was performed on 432 women with histological diagnosis of CIN2+ who were treated with LLETZ from 1996 to 2020 and followed-up until October 2021 at Hospital Bellvitge in Barcelona, Spain. Age, surgical margins, 6-month HR-HPV, excision type, and cone volume/dimensions were ana-lyzed in association with follow-up detection of CIN2+. The cumulative probability of follow-up detection of CIN2+ was calculated by Kaplan-Meier and Cox models. Results: CIN2+ was detected in 7.4% of cases, with over 90% found within 5 years post-LLETZ. HR-HPV (HR = 7.36, 95% CI = 3.55-15.26), involved margins (HR = 3.94, 95% CI = 1.68-9.25), uncertain margins (HR = 4.42, 95% CI = 1.55-12.55), and age ≥ 35 years (HR = 2.92, 95% CI = 1.19-7.13) were predictors of follow-up detection of CIN2+. Type 3 excision (p-value = 0.035) and cone length (p-value = 0.010) correlated with clear margins. The negative predictive value (NPV) of both negative HR-HPV post-LLETZ and clear margins was 98.7%. Conclusions: Negative HR-HPV post-LLETZ and clear margins provide stronger reassurance against follow-up detection of CIN2+ than LLETZ characteristics. Larger ex-cisions in older women likely reduced the risk of involved margins. Close surveillance, including repeated HR-HPV testing within the first 5 years post-LLETZ, is crucial.