We report a case of giant condyloma with malignant degeneration. A 56-year-old male was referred to our hospital due to a penile infection that was resistant to antibiotic therapy for more than a year. The swelling appeared to be a penile cancer. We suspected malignancy and performed penile biopsies twice; however, the histopathological diagnosis was condyloma acuminatum and malignant findings were absent. We continued the antibiotic therapy for 3 months; however, no improvement was achieved. Therefore, total penectomy and urinary diversion were performed. The pathological diagnosis of the resected tissues was not only condyloma but also squamous cell carcinoma, and cancer cells appeared on the cut surface of the specimens. We added radiation therapy. There was no evidence of recurrence or metastasis at 18 months after surgery.