High-grade squamous intraepithelial lesion (HSIL) is a precancerous lesion that requires timely and effective intervention. Photodynamic therapy (PDT) using 5-aminolevulinic acid (ALA) has emerged as a non-invasive, fertility-preserving alternative to excisional procedures. However, the ALA-PDT regimen remains to be optimized. To compare the efficacy and safety of three treatment strategies-three-session PDT (3PDT), six-session PDT (6PDT), and a single CO This retrospective cohort study included 158 women aged 20-45 years with biopsy-confirmed cervical HSIL/CIN2. Participants received one of three regimens: 3PDT (n = 49), 6PDT (n = 47), or Laser + 6PDT (n = 54). Lesion regression and high-risk HPV (hrHPV) clearance were assessed at 3-6 and 9-12 months post-treatment. A subset of patients was followed up to 18-24 months. Adverse events were also recorded. At the 3-6 months follow-up, the complete remission (CR) rates were 67.35 % (3PDT), 74.47 % (6PDT), and 79.63 % (Laser + 6PDT), with hrHPV clearance rates of 67.35 %, 72.34 %, and 77.78 %, respectively. Differences among groups were not statistically significant (P > 0.05). By 9-12 months, CR rates reached ≥90 % in all groups, and hrHPV clearance exceeded 80 %. At 18-24 months, hrHPV clearance reached 100 % in the 6PDT group, while three patients in the 3PDT group experienced HPV recurrence. All regimens were well tolerated, with only mild adverse events reported. All three ALA-PDT-based regimens were effective and safe in treating HSIL/CIN2 in reproductive-age women. Although not statistically significant, six-session PDT with or without laser pretreatment showed a trend toward higher lesion remission and hrHPV clearance. Individualized treatment decisions based on disease severity, patient preference, and cost factors are recommended to optimize outcomes.