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Simple Summary: Women diagnosed with cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and treated by excisional procedures remain at high risk for recurrence over time. "Treatment failure" has been reported in up to 23% of women within two years after treatment. The aim of this study was to investigate the impact of HPV same genotype persistence on CIN2+ recurrence. Our findings confirm that HPV same genotype persistence has 30-fold increased odds of developing CIN2+ recurrence (p < 0.001), whereas histological grade, glandular crypt involvement, and margin status are not significantly related with treatment failure. Persistence of multiple genotypes and of HPV 16/18 with or without other HR genotypes show a significant impact on relapse free survival. HPV genotyping as "test-of-cure" enables a personalized risk-based management, by identifying women at higher risk of relapse who need intensive follow-up and avoiding risk of over-treatment in women with new HPV genotype infection after surgery. To evaluate the significance of HPV persistence as a predictor for the development of CIN2+ recurrence and the impact of multiple genotypes and of HPV 16/18 on recurrence risk. A prospective cohort observational study was carried out at the European Institute of Oncology, Milan, Italy, from December 2006 to December 2014. A total of 408 women surgically treated by excisional procedure for pre-neoplastic and neoplastic cervical lesions were enrolled. HPV test was performed at baseline and at first follow-up visit planned at 6 ± 3 months after treatment. Two-year cumulative incidences for relapse were estimated and compared by the Gray's test. Overall, 96 (23.5%) patients were persistent for at least one genotype at three to nine months from baseline and 21 (5.1%) patients relapsed. The two-year cumulative relapse incidence was higher in HPV persistent patients compared to not-persistent (CIF = 27.6%, 95% CI: 16.2–40.2% versus CIF = 1.7%, 95% CI: 0.3–5.8%, p < 0.001), in women with persistent multiple infections (CIF = 27.2%, 95% CI: 7.3–52.3%, p < 0.001), and with the persistence of at least one genotype between 16 and 18, irrespective of the presence of other HR genotypes (CIF = 32.7%, 95% CI: 17.9–48.3%, p < 0.001), but not significantly different from women positive for single infections or any other HR genotype, but not for 16 and 18. The risk of CIN2+ recurrence should not be underestimated when same HPV genotype infection persists after treatment. [ABSTRACT FROM AUTHOR]