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Intraepithelial neoplasia of the female genital tract has long been associated with human papillomavirus infection. To date, there have been no previously published studies of oral dysplasia that have identified light microscopic features predictive of the presence of human papillomavirus. We identified a variant of oral epithelial dysplasia, koilocytic dysplasia, that exhibited light microscopic features suggestive of HPV infection. To determine if these microscopic features were specifically correlated with human papillomavirus infection, DNA in situ hybridization for human papillomavirus 6/11, 16/18, and 31/33/51 was performed on 31 lesions diagnosed histologically as koilocytic dysplasia. Seventeen matched control cases of conventional oral epithelial dysplasia were also analyzed for human papillomavirus. Human papillomavirus DNA was detected significantly more often (p < 0.001) in koilocytic dysplasia (80.6%) than conventional oral epithelial dysplasia (0.0%). Positive cases of koilocytic dysplasia contained either intermediate-risk (31/33/51) or high-risk (16/18) human papillomavirus types whether or not they contained low-risk human papillomavirus types (6/11). The histologic and clinical presentation of koilocytic dysplasia was unique. Lesions demonstrated koilocytes and other microscopic characteristics of human papillomavirus infection, as well as features of conventional epithelial dysplasia. A striking male predominance was noted, as was a relatively young average age of presentation (39.0 years). On the basis of our preliminary analysis, we conclude that oral koilocytic dysplasia represents a unique pathologic entity and that the presence of human papillomavirus can be predicted on light microscopy with at least 80% accuracy. The clinical significance and potential for malignant transformation of koilocytic dysplasia remain to be investigated.