The purpose of this study was to correlate the histological findings and clinical information for vulvar precancers and cancers with the detection of human papillomavirus (HPV). Forty-five squamous cell lesions (twenty-two high-grade squamous intraepithelial lesions (SILs) and twenty-three invasive cancers) were analyzed for HPV DNA after amplification by the polymerase chain reaction. HPV DNA was noted in 13/22 (59%) high-grade SILs and 7/23 (30%) invasive cancers. For the invasive cancers, HPV DNA was detected in 0/13 that had substantial keratinization compared to 7/10 with minimal keratinization. Adjacent SIL was noted in 6/7 (86%) HPV-positive cancers compared to 1/16 (6%) in the HPV negative group. The mean age of the two groups was equivalent. The rate of metastases (3/7, 43%) for the HPV-positive group was higher than that for the HPV-negative (4/16, 25%) group. We conclude that vulvar cancers, unlike squamous cell carcinoma of the cervix, which is associated with HPV DNA in most cases, can be differentiated into two groups on the basis of histological findings and presence of HPV DNA.