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Persistent infection with human papillomavirus (HPV) causes almost all cervical precancerous lesions and cancers. Bivalent, quadrivalent, and nonavalent HPV vaccines effectively prevent high-grade cervical intraepithelial neoplasia (CIN3). The effectiveness of HPV vaccination against CIN3 is 97–100% in HPV-naïve populations and 44–61% in the overall population. Although HPV vaccination has substantially reduced the incidence of cervical cancers, several cases of precancerous cervical lesions in HPV-vaccinated patients have been reported. We report the clinical case of a 19-year-old woman whose first Pap smear was diagnosed as a high-grade squamous intraepithelial lesion (HSIL) after quadrivalent HPV vaccination. Colposcopy and cervical biopsy were performed, revealing HSIL/CIN3. Our multidisciplinary team decided to take a conservative approach with follow-up visits with cervical biopsies of this young patient. After six months, spontaneous regression of high-grade cervical dysplasia was observed. Although HPV immunization has shown to be extremely effective in preventing a high proportion of cervical precancerous lesions and cervical cancers, HPV vaccines do not protect against all oncogenic high-risk HPV genotypes. Consequently, healthcare providers must encourage HPV-vaccinated women to still regularly attend national cervical screening programs. [ABSTRACT FROM AUTHOR]