Background <p>The optimal management of women with non-16/18 hrHPV infection and normal cytology remains a topic of clinical debate. While immediate colposcopy is often considered, current international guidelines recommend a follow-up approach. This study aimed to evaluate the effectiveness of immediate colposcopy in detecting high-grade lesions in this intermediate-risk population.</p> Methods <p>This retrospective study included 454 unvaccinated women with non-16/18 hrHPV positivity and normal cytology results. Immediate colposcopic biopsy was performed in 142 patients with abnormal colposcopic findings. The remaining 312 women with normal colposcopy were followed with repeat hrHPV testing and cytology at 12 months. Those with persistent infection underwent colposcopy and biopsy if indicated. Histopathological and clinical outcomes were compared between the immediate and delayed colposcopy groups.</p> Results <p>CIN2 + lesions were identified in 10 patients (7.0%) within the immediate colposcopy group. Of the 276 women in the non-biopsy group who completed follow-up, 89 (32.2%) showed persistent hrHPV infection, and 29 underwent colposcopic biopsy. No CIN2 + lesions were detected in this delayed evaluation group. The difference in CIN2 + detection rates between the two groups was statistically significant (<i>p</i> = 0.033). Persistent hrHPV infection was more frequently observed in CIN2 cases than in CIN3, although this difference was not statistically significant (<i>p</i> = 0.545).</p> Conclusions <p>All high-grade lesions in this cohort were detected at initial colposcopy, whereas delayed colposcopic evaluation after documented persistence yielded no additional CIN2 + diagnoses. These findings support the safety of a follow-up-based management strategy and suggest that colposcopic referral should be guided by hrHPV persistence rather than initial positivity alone. This approach may help reduce overtreatment and optimize resource use in populations with low HPV vaccination coverage.</p>