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We describe here a case of high-grade vaginal squamous lesion in a 54-year-old woman with a papillomaviruses (HPV) genital infection that developed from a cervical low-grade squamous intraepithelial lesion (SIL) to a high-grade SIL (H-SIL) on cytological examination. A colposcopy exam led to the detection of suspect vaginal lesions with granulomatous infiltrations, which were classified as a Vaginal Intra-Epithelial Neoplasia grade 2 after pathologists' analyses. After a laser vaginal surgery and a loop excision of the transformation zone, the analyses of the anatomical pieces using a near-complete HPV screening panel revealed an HPV-4 infection that was not detected before in cervical smears. This HPV-infection is associated with a high human herpesvirus type 6A (HHV-6A) viral load in the same anatomical piece. The presence of an inherited chromosomally integrated HHV-6A (iciHHV-6A) was proved in this patient by real-time polymerase chain reaction on hair follicles and nail. This case suggests reconsidering both the benign nature of low-grade lesions in the female genital tract and the well-known "good" prognosis of low-risk HPV infection, especially when iciHHV-6A is diagnosed. This clinical course insists on the benefits of the multiplex panel use or global sequencing in order to optimize biological testing sensitivity, and so enhance clinical management of infection-induced neoplasia., (© 2017 S. Karger AG, Basel.)