Persistent infection with high-risk human papillomavirus (HR-HPV) following cervical cancer surgery poses a significant risk for disease recurrence and progression to vaginal intraepithelial neoplasia. This retrospective cohort study evaluated the comparative efficacy of Paiteling, a Traditional Chinese Medicine compound, versus recombinant human interferon gel in treating persistent HR-HPV infection post-hysterectomy. Thirty-six patients with persistent HR-HPV positivity were allocated to either Paiteling (n=17) or interferon (n=19) treatment groups. Comprehensive assessment included HPV DNA load, ThinPrep cytologic test results, and colposcopic findings at baseline, 6-month, and 12-month follow-ups. At 6 months, the interferon group demonstrated significantly higher cure rates (68.4% vs 17.6%, 2=7.646, p=0.006). However, a remarkable reversal was observed at 12 months, with Paiteling achieving superior clearance rates (94.1% vs 63.2%, 2=4.976, p=0.044). Multivariable analysis confirmed Paiteling treatment as a strong predictor of HPV clearance (adjusted OR=9.52, 95% CI: 1.11-220.32, p=0.039). Subgroup analysis revealed consistent treatment effects across all HPV genotypes. Adverse events were mild and self-limiting, with no significant differences between groups (29.4% vs 10.5%, p=0.226). This study demonstrates Paiteling’s superior long-term efficacy for persistent postoperative HR-HPV infection, characterized by a unique delayed-but-sustained response pattern. The multi-targeted mechanism, favorable safety profile, and sustained viral clearance support Paiteling’s potential as an effective therapeutic option in postoperative management, though validation through larger prospective trials is warranted.