Six men with either recurrent (n = 4) or unresectable (n = 2) squamous cell carcinoma of the penis (n = 5) and urethra (n = 1) received chemotherapy with cisplatin intravenously at a dose of 100 mg/m2. This was followed 24 hours later by a continuous intravenous infusion of 5-fluorouracil (5-FU) at a dose of 960 mg/m2/d for five days every 3 to 4 weeks. There was universal alopecia. The other toxicities were mild and consisted of mucositis, nausea, vomiting, reversible creatininemia, and transient azotemia. After chemotherapy, five patients had a clinical partial response and one had a complete response. Of the five patients with no metastases, three had residual unresectable tumors. These three patients received radiation and survived for 6, 8, and 20 months after the start of chemotherapy. The other two patients were rendered disease-free by surgery. The first patient, who was a partial responder to chemotherapy, survived for 26 months. The second patient, who was a clinical complete responder, had excision of microscopic disease and is disease-free at 32+ months after the start of chemotherapy. This is the first article to report that the combination of cisplatin and 5-FU is active in penile and urethral carcinomas. After chemotherapy, surgery may be useful in selected patients to accurately assess response and excise localized residual tumors. Patients rendered tumor-free may achieve long-term survival.