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Simple Summary: Long-term population-based studies have demonstrated that the risk of cervical cancer after conization for CIN3 treatment persists for at least 25 years, underscoring the need for careful follow ups and the importance of detecting residual disease after LEEP. Data from the literature show that positive-margin and post-treatment HPV persistence are predictors of residual disease. The management of these cases determines the use of a second LEEP or an accurate follow up, but the risk of overtreatment or of not treating an occult carcinoma exists. Our goal was to discover an efficient method to select patients requiring a second LEEP from those requiring a follow up (FU) only through the use of E6/E7 HPV mRNA search. This prognostic marker allowed us to identify women with residual disease (CIN2+) and treat them with a second LEEP. At the same time, it helped us identify E6/E7-mRNA-negative women as patients at low risk of progression, potentially avoiding further treatment and subjecting them to a follow up only. The risk of overtreatment or not treating an occult carcinoma exists in women at risk of residual disease after a LEEP excision for CIN3. Our goal was to discover an efficient method to select patients requiring a second LEEP from those requiring a FU only through an mRNA-detection test. In a population of 686 women undergoing a LEEP excision for CIN 3, we selected 285 women at risk of residual disease and subjected them to a search for E6/E7 mRNA HPV. The women with negative mRNA were subjected to a follow up, while the women with positive mRNA were subjected to a second LEEP. The histological examination of the second cone revealed 120 (85.7%) cases of residual disease in the mRNA-positive women: 40 cases of CIN2, 51 cases of CIN3, 11 cases of squamous microinvasive carcinoma, 7 cases of squamous carcinoma, 9 cases of AIS (adenocarcinoma in situ) and 2 cases of adenocarcinoma. Among the mRNA-negative women undergoing a follow up, there were only five cases of residual disease. During the follow-up period of about 6 years, we witnessed the regression of the residual disease and the elimination of the virus, just as predicted by the negative result of the mRNA test. Testing patients for E6/E7 mRNA allowed us to identify women with residual disease (CIN2+) and treat them appropriately. [ABSTRACT FROM AUTHOR]