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Preinvasive squamous neoplasms of the lower genital tract are currently classified using a two-tier system (high- or low-grade squamous intraepithelial lesion) as directed by the Lower Anogenital Squamous Terminology (LAST) guidelines but may also be subclassified as intraepithelial neoplasia grade 1 (−IN1), −IN2, or −IN3. The LAST recommended that all diagnoses of −IN2 be supported by immunohistochemistry (IHC) for p16. We examined whether p16 and Ki-67 IHC are necessary to diagnose −IN2 when the lesion has obvious high-grade histology.p16 and Ki-67 IHC were performed prospectively and retrospectively on vulvar, vaginal, and cervical specimens with an initial diagnosis of −IN2 based on hematoxylin and eosin morphology, and a final diagnosis was made after consensus review.Five of 46 prospective and four of 38 retrospective cases were p16 negative. The diagnosis of −IN2 was maintained in eight of these nine cases because of compelling high-grade squamous intraepithelial lesion histology. Overall, p16 and Ki-67 IHC altered the −IN2 diagnosis to a lower grade in only one of 84 cases (1.2%, <0.01%–7.1%). Moreover, p16 was positive in all cases where the preanalytic impression was of −IN2/3 (13/13).p16 IHC lacks utility in cases of morphologically obvious −IN2, because the stain is positive in most cases. The LAST recommendation to use p16 IHC to support all diagnoses of −IN2 will result in performing the immunostain in many circumstances where it is not medically necessary. Among cases that are p16 negative, many have compelling high-grade morphology. The LAST perspective that the stain trumps histology may allow false-negative IHC results to prevail.