The goal of this study was to evaluate the histologic criteria used to establish the diagnosis of human papillomavirus (HPV)-associated disease, especially in borderline lesions. In a completely blinded study, 21 patients had one biopsy each of the cervix and vulva. Each specimen was evaluated by RNA and DNA in situ hybridization, a histologic diagnosis was rendered, and then each was evaluated for 12 histologic criteria commonly associated with HPV. On the cervix only binucleation and dysplasia correlated well with in situ hybridization. Koilocytosis correlated very strongly with the histologic diagnosis. On the vulva, koilocytosis, papillomatosis, elongated rete pegs, binucleation, and hypergranulosis correlated well with in situ hybridization. When four other pathologists reviewed the slides, they agreed on the histologic diagnosis and the presence of koilocytosis, binucleation, and dysplasia on the cervix but on none of the other criteria. On the vulva the pathologists disagreed on the overall diagnosis and the presence of any of the criteria with the exception of papillomatosis. Nonclassic histologic criteria should not, by themselves, be used to make the diagnosis of condyloma. The use of such terminology as "suggestive of condyloma" in histologic diagnoses should be avoided in favor of more descriptive terminology to avoid possibly unnecessary treatment for lesions of questionable significance.