OBJECTIVETo compare and analyze the efficacy as well as adverse effects of 5-aminolevulinic acid photodynamic therapy (5-ALA-PDT) and carbon dioxide (CO₂) laser therapy in the treatment of vaginal intraepithelial neoplasia II (VaIN II), and assess the feasibility, safety, and influencing factors of ALA-PDT.METHODSA retrospective review was conducted on the clinical data of 79 patients with VaIN II (PDT group = 37, Laser group = 42) who were treated at the Gynecology Department of the Affiliated Hospital of Qingdao University from January 2022 to January 2024. Follow-up evaluations were carried out at 3, 6, and 12 months after treatment. During these follow-ups, human papillomavirus (HPV) testing, cervical liquid-based cytology (TCT), colposcopy, and vaginal lesion biopsy were utilized to assess key outcomes, including the lesion reversal rate, HPV clearance, and treatment-related adverse reactions in both groups.RESULTSThe lesion reversal rates following ALA-PDT treatment were 83.3%, 86.1%, and 88.2% at 3, 6, and 12 months, respectively. There was no significant difference when compared to the laser group. However, the negative HPV conversion rates at 6 and 12 months after ALA-PDT treatment were 73.5% and 87.5%, respectively, which were significantly higher than those observed in the CO2 laser group (P < 0.05). Adverse events related to photodynamic therapy occurred in 13.5% (5/37) of the cases, which was significantly lower than the 35.7% (15/42) in the laser group. In the laser group, increased incidences of vaginal bleeding and scarring were observed. Logistic univariate regression analysis revealed that factors such as a disease duration of more than 1 year, multifocal lesions, and a history of cervical cancer or precancerous surgery negatively influenced lesion reversal at 6 months after ALA-PDT treatment (P < 0.05). Additionally, factors like patient age over 50 years old (menopause), having more than two pregnancies, an imbalance in the vaginal microbiota, a prolonged HPV infection (lasting more than 1 year), and HPV superinfection affected HPV clearance at 6 months after ALA-PDT treatment (P < 0.05).CONCLUSIONFor the treatment of VaIN II, ALA-PDT exhibits equivalent lesion reversal rates and superior HPV clearance compared to CO2 laser treatment, while causing minimal anatomical disruption to the vaginal tissue.