Purpose <p>To compare the efficacy and safety of 5-Aminolevulinic Acid Photodynamic Therapy (5-ALA-PDT) and Loop Electrosurgical Excision Procedure (LEEP) in the treatment of cervical high grade squamous intraepithelial lesions (HSIL).</p> Methods <p>The data of 116 patients with pathologically diagnosed cervical HSIL in Hangzhou First People’s Hospital from January 2020 to June 2023 were retrospectively analyzed. According to the treatment methods, they were divided into 5-ALA-PDT group (50 cases) and LEEP group (66 cases). The patients were followed up at 3 months, 6 months, and 12 months after treatment. The clinical data of the two groups were compared.</p> Results <p>There were no significant differences in baseline data between the two groups of patients (<i>P</i> &gt; 0.05). At 12-month follow-up the complete remission (CR) rate of LEEP group and 5-ALA-PDT group was 93.94% (62/66) and 86.00% (43/50) (<i>P</i> = 0.260), respectively. The HPV clearance rate of LEEP group and 5-ALA-PDT group was 66.67% (44/66) and 80.00% (40/50) (<i>P</i> = 0.112), respectively. Multivariate analysis revealed that endocervical canal involvement was a significant risk factor for 5-ALA-PDT failure (OR = 27.35, 95% CI: 3.512–43.390, <i>P</i> = 0.012) and persistent HPV infection (OR = 8.013, 95% CI: 2.045–36.901, <i>P</i> = 0.011). In terms of adverse reactions, most of the reactions in 5-ALA-PDT group were mild local reactions that could be relieved within one week. The proportion of bleeding and cervical scar formation was higher in patients in the LEEP group (<i>P</i> &lt; 0.05).</p> Conclusion <p>5-ALA-PDT and LEEP exhibit potential similarity in efficacy in the treatment of cervical HSIL, but the former has milder adverse reactions. The involvement of the endocervical canal is a significant risk factor for both 5-ALA-PDT failure and persistent HPV infection.</p>