The diagnosis of a vulvar condyloma is made when perinuclear halos are seen with nuclear atypia and binucleate forms (koilocytotic atypia). These changes are most prominent in the granular layer and are associated with the presence of human papillomavirus (HPV). However, these changes may be absent or minimal in patients with papillary vulvar lesions; this situation can thus present diagnostic difficulties. We analyzed the histologic features of 53 biopsies from 48 patients who had vulvar lesions suggestive of condylomata. Of the 26 biopsy specimens with koilocytotic atypia, 20 (77%) had sequences homologous to HPV DNA as detected by Southern blot hybridization analysis using a probe of HPV s 6/11, 16, 18, 31, 35, and 51. In cases where the histologic features were suggestive but not diagnostic of condylomata, because unequivocal koilocytotic atypia was not noted, five of 27 (19%) had detectable HPV DNA. In this latter group, we found no histologic feature to distinguish the cases that had detectable HPV DNA from those that did not. Analysis for HPV DNA by in situ hybridization in the cases that were histologically equivocal for condyloma was uniformly negative. We conclude that there is a marked decrease in the detection rate of the HPV types associated with genital tract neoplasms in vulvar lesions that lack koilocytotic atypia. Southern blot hybridization analysis was the only reliable way to distinguish the "equivocal for condyloma" cases that had HPV from those where HPV DNA was not detected.