Abstract: Objective To analyze the influencing factors of the recurrence of cervical high-grade squamous intraepithelial lesion (HSIL) after cold knife conization.Methods A total of 368 patients with HSIL who were admitted to Tangshan Gongren Hospital and Tangshan Maternal and Child Health Care Hospital from January 2015 to June 2020 were enrolled and their clinicopathological and follow-up data were analyzed. All the patients underwent cold knife conization. The levels of human papillomavirus (HPV) E6/E7 mRNA were detected before operation and after operation regularly. The expression of typeⅡA topoisomerase (TOP2A) and p16 was detected by immunohistochemistry. The risk factors of recurrence were analyzed.Results The recurrence rate of the HPV E6/E7 mRNA persistent infection group was significantly higher than that without persistent infection (25.4% vs 6.3%, P<0.05). The recurrence rate of the TOP2A high expression group was significantly higher than that with TOP2A low expression (12.5% vs 2.9%, P<0.05). Age, quadrant involvement, gland involvement, histological grade and p16 expression were not associated with recurrence (P>0.05). Logistic regression analysis showed that HPV E6/E7 mRNA persistent infection and high expression of TOP2A were the independent risk factors for postoperative recurrence (OR=4.989, OR=3.883, P<0.05). There was no difference in the recurrence rate among different types of HPV persistent infection (P>0.05). HPV E6/E7 mRNA persistent infection was positively related to high expression of TOP2A (P<0.05).Conclusions HPV E6/E7 mRNA persistent infection and high expression of TOP2A are the high risk factors for recurrence of cervical HSIL after cold knife conization, and the two factors may have intrinsic relationship in the mechanism of recurrence. Detection of HPV E6/E7 mRNA persistent infection and expression of TOP2A can facilitate the postoperative management of cervical HSIL.