A 54-year-old man presented with a polypoid mass involving the right side of the penis glans, which had developed over a period of approximately 8 months. The lesion was itchy with purulent secretions. It was associated with a swollen right inguinal lymph node and a weight loss of 9 kg over the previous 6 months. The patientβs sexual history was notable for unprotected intercourse with multiple partners. Serologic tests were negative for various sexually transmitted infections, including human immunodeficiency virus infection. Biopsies of both the lesion and the lymph node were performed, and a diagnosis of squamous-cell carcinoma with presence of human papillomavirus (HPV) serotype 18 was made. Surgery (excision of the lesion, with a local flap used for coverage of the soft-tissue defect) was performed with satisfactory results. HPV is a known cause of cervical cancer in women. HPV infection can also affect men and can cause penile cancer, although its prevalence is lower than that of cervical cancer among women. Primary prevention, education, and vaccination are important to reduce the occurrence of HPV infection and associated cancers.