Oral koilocytic dysplasia (KD), described in 1996 as an entity of unknown biologic potential, exhibits histologic features of both human papillomavirus (HPV) infection and oral epithelial dysplasia. Histologic features of HPV infection include koilocytosis, acanthosis, multinucleated keratinocytes, and atypical mitoses. HPV 6/11 may be present in KD, but high-risk HPV types, including HPV 16/18/31/33, were consistently found in cases shown to be HPV-positive in the original study. We report 2 cases of oral KD found to be in continuity with squamous cell carcinomas (SCC). A 41-year-old nonsmoking male dentist with a negative history for regular alcohol intake presented with a 2.7-cm lateral tongue leukoplakia. Clinical impression was oral appliance related traumatic hyperkeratosis. Diagnosis on biopsy was epithelial dysplasia, mild, with features of HPV (KD). SCC was found at reexcision, and a lateral neck lymph node was positive for metastases. The biopsy specimen was positive for HPV DNA using PCR. Sequencing for HPV subtype identification was unsuccessful, interpreted to be owing to infection with multiple HPV subtypes. A second case of KD with histologic transition to SCC was identified in a 64-year-old male, also as a lateral tongue leukoplakia (2.5 cm). Social history was positive for smoking (2.5 packs/day) and daily alcohol intake. Clinical impression was epithelial dysplasia without appreciable lymphadenopathy. Biopsy revealed SCC in transition from KD. The biopsy specimen was positive for HPV 16 DNA (PCR and DNA sequencing). Definitive conclusions cannot be drawn regarding the role of HPV in the pathogenesis of these SCCs. However, the intimate associations of SCC with lesions fulfilling the histologic and microbiologic criteria for oral KD document the potential for KD to be associated with oral cancer. Oral koilocytic dysplasia (KD), described in 1996 as an entity of unknown biologic potential, exhibits histologic features of both human papillomavirus (HPV) infection and oral epithelial dysplasia. Histologic features of HPV infection include koilocytosis, acanthosis, multinucleated keratinocytes, and atypical mitoses. HPV 6/11 may be present in KD, but high-risk HPV types, including HPV 16/18/31/33, were consistently found in cases shown to be HPV-positive in the original study. We report 2 cases of oral KD found to be in continuity with squamous cell carcinomas (SCC). A 41-year-old nonsmoking male dentist with a negative history for regular alcohol intake presented with a 2.7-cm lateral tongue leukoplakia. Clinical impression was oral appliance related traumatic hyperkeratosis. Diagnosis on biopsy was epithelial dysplasia, mild, with features of HPV (KD). SCC was found at reexcision, and a lateral neck lymph node was positive for metastases. The biopsy specimen was positive for HPV DNA using PCR. Sequencing for HPV subtype identification was unsuccessful, interpreted to be owing to infection with multiple HPV subtypes. A second case of KD with histologic transition to SCC was identified in a 64-year-old male, also as a lateral tongue leukoplakia (2.5 cm). Social history was positive for smoking (2.5 packs/day) and daily alcohol intake. Clinical impression was epithelial dysplasia without appreciable lymphadenopathy. Biopsy revealed SCC in transition from KD. The biopsy specimen was positive for HPV 16 DNA (PCR and DNA sequencing). Definitive conclusions cannot be drawn regarding the role of HPV in the pathogenesis of these SCCs. However, the intimate associations of SCC with lesions fulfilling the histologic and microbiologic criteria for oral KD document the potential for KD to be associated with oral cancer.