Vaginal warts (condylomata) secondary to human papillomavirus (HPV) infection are most easily identified when perinuclear halos are seen with clear-cut nuclear atypia (koilocytotic atypia) in the superficial cells of the lesion. However, vaginal lesions clinically resembling condylomata may exhibit lesser degrees of nuclear atypia with findings suggestive of, but not typical for, the presence of HPV. The diagnosis and management of such lesions are unclear. We correlated histologic findings with the detection of HPV DNA sequences in 39 vaginal lesions that contained a spectrum of clinical and histologic features suggestive of, or diagnostic for, condyloma. We detected HPV DNA in 63% (N = 22) of lesions with koilocytotic atypia and in 11.7% (N = 17) of lesions that showed some histologic features suggesting condyloma but that lacked koilocytotic atypia. These findings imply that vaginal lesions lacking koilocytotic atypia are not always caused by HPV, emphasizing the need for a conservative approach when the diagnosis of vaginal condyloma is not clear-cut.