Lichen sclerosus, an unusual chronic mucocutaneous condition of the penis, has been found in association with invasive penile cancer, and squamous cell carcinoma has been reported in patients with longstanding lichen sclerosus. The aim of this study was to determine the anatomic distribution and prevalence of lichen sclerosus in patients with squamous cell carcinoma of the penis and to search for a correlation with special types of carcinomas. Clinical and pathologic data from 207 penectomy and circumcision specimens with squamous cell carcinomas and giant condylomas were evaluated, and 68 patients with lichen sclerosus were identified. Mean age was 61 years. The preferential anatomic site of lichen sclerosus was the foreskin, but other sites (glans and coronal sulcus) including urethra were also involved. Grossly, the lesions showed white-gray smooth or irregular patches and plaques adjacent to invasive cancers. Microscopically, the lesion was stromal-epithelial with atrophic and hyperplastic epithelium and edematous or densely eosinophilic hyalinized lamina propria. A variable band of lymphocytic infiltration beneath the sclerosis was noted. Lichen sclerosus were preferentially associated with non-human papillomavirus variants of squamous cell carcinoma. When lichen sclerosus was associated with malignancy, it often showed, in addition to the hyperplastic epithelium, a low-grade squamous intraepithelial lesion. These findings suggest that lichen sclerosus may represent preneoplastic condition for at least some types of penile cancers, in particular those not related to human papillomavirus.