BACKGROUND & OBJECTIVE: Human papillomavirus (HPV) is a major cause of cervical cancer and mortality, particularly in low-income countries. Late diagnosis of cervical cancer often leads to advanced-stage disease, resulting in poorer prognosis and higher mortality, which underscores the critical need for effective early screening methods. Pap smears, colposcopy, and HPV testing are essential for early detection. This study addresses a gap in the literature by comparing the effectiveness of different diagnostic methods specifically in women with multiple high-risk HPV (hrHPV) infections-a population for which limited comparative data exist. METHODS: This prospective cross-sectional study, approved by the Ethical Committee of Qazvin University (IR.QUMS.REC.1400.143), was conducted at Kowsar Hospital from 2022 to 2023 and included 608 patients infected with multiple hrHPV subtypes. Inclusion criteria required hrHPV confirmation by PCR genotyping and excluded patients without colposcopy and biopsy or with a history of cervical dysplasia. Participants underwent Pap smear cytology, colposcopy, and biopsy, with the biopsy specimens examined by a gynecologic pathologist. Statistical analyses included chi-square tests for qualitative variables and t-tests or ANOVA for quantitative variables, with a significance level set at P<
0.05. RESULTS: The average age of the patients was 38.54 years, with the majority aged 30-39 years (43.6%). Common symptoms included vaginal discharge (36.5%) and postcoital bleeding (34.9%). Pap smear results showed ASCUS in 43.6% of cases and LSIL in 39.1%. Colposcopy revealed acetowhite lesions in 45.6% and abnormal vascular patterns in 25.5%. Histopathology indicated that 72.4% of patients had CIN I. Smoking was significantly correlated with colposcopic findings (P=0.044). Colposcopy demonstrated the highest sensitivity (69.1%) for detecting cervical lesions, while cytology had the highest specificity (63.1%). CONCLUSION: Pap smear findings provide adequate diagnostic accuracy for hrHPV patients, but colposcopy offers superior sensitivity for detecting cervical lesions. Combining both methods is recommended to improve diagnosis.