The classic histologic presentation of epidermodysplasia verruciformis is a verruca plana-type lesion with minimal hyperkeratosis and acanthotic areas where the cells contain perinuclear halos and blue-gray pallor. Whereas these lesions have a high malignant potential, it is important to elucidate the histologic spectrum of this entity and to differentiate it from its mimics. Fifteen skin biopsies from people with multiple cutaneous warts clinically suspicious for epidermodysplasia verruciformis were analyzed both histologically and for human papillomavirus (HPV) deoxyribonucleic acid (DNA) by in situ hybridization. Ten of the lesions contained HPV DNA, either type 5 (n = 6), type 8 (n = 3), or type 51 (n = 1). Only three of these lesions showed typical verruca plana. The histologic marker of HPV DNA in the other seven viral-positive cases was rare perinuclear halos in association with an irregular granular layer. The other five cases, which were also negative for viral DNA after polymerase chain reaction in situ hybridization, rarely demonstrated the abrupt variation in keratohyaline granules and concomitant perinuclear halos. The authors conclude that there is a wide spectrum of histologic changes in epidermodysplasia verruciformis and that viral testing in conjunction with the histologic and clinical findings can differentiate this premalignant entity from its mimics.