Verrucous lesions in patients with human immunodeficiency virus (HIV) disease may be caused by viruses other than the human papillomavirus. We describe a 32-year-old HIV-positive black man who presented with a verrucous lesion of the intergluteal cleft that clinically resembled condyloma acuminata or verrucous carcinoma. Histopathological examination revealed the changes of herpes virus infection, and culture of the tissue confirmed the presence of herpes simplex virus. Human papillomavirus was not detected by in situ hybridization or the polymerase chain reaction. Significant regression of the lesion was seen after 6 weeks of treatment with oral acyclovir.