Clinical and experimental data suggest a synergistic antitumoral effect with the combined treatment of radiotherapy and 5-fluorouracil (5-FU) serving as a radiosensitizer. This combined modality was studied in 30 malignant melanoma patients with advanced locoregional or isolated, bulky, soft-tissue or visceral metastases. All patients were symptomatic, pain being the chief complaint, followed by symptoms related to large tumors. Treatment was given on an ambulatory basis, twice weekly, and consisted of 5-FU, 500 mg/m2 administered in 8-h i.v. drip infusion, followed by radiotherapy 8 h after completion of the 5-FU administration. 60Co teleunit, delivering 400 rad per dose per fraction, was given over 6 1/2 weeks to a total of 5,200 rad. The overall response rate was 70% (21 of 30 patients). Three patients (10%) achieved a complete response lasting from 3 to 11 months, and 18 (60%) achieved a partial response lasting from 3 to 13 months. The response rate was 82% for skin, 75% for lymph node, and 43% for visceral metastases. Symptomatic relief was obtained in 83% (25 of 30) of the patients. This palliative therapy was well-tolerated, and patients were able to maintain their routine lifestyles throughout. Only in one patient was 5-FU abandoned after 3 weeks, due to cardiac ischemia. Similar response rates have only been achieved with radiotherapy alone employing individual fractions of 600 rad or higher. Since the 5-FU we added is known to have a very limited effect on malignant melanoma, this study suggests its potential as a radiosensitizer in malignant melanoma.