The study, which compares DDP to DDP + FU, was planned to detect an increase by 60% in efficacy and by 5% in toxicity (2a = B = 5%) for DDP + FU. In a previous trial DDP produced 15% of responders and 5% of high-level toxic manifestations. The eligible patients with an advanced head and neck cancer were paired off successively on the basis of the tumour site and the UICC stage. DDP (100 mg/m2; day 1) was administered with hyperhydration, alone in the first protocol and followed by a 5-day continuous infusion of 5-FU (1 g/m2) in the second one. Courses were repeated every three weeks. Assessment was carried out after three courses or two, in cases of toxic manifestations. Seventy-four patients, who were paired off, entered the trial. The median age was 55 years and the median Karnofsky index was 90. The tumor site was as follows: 28 hypopharynx, 28 oropharynx, 8 oral cavity, and 10 multiple primary cancers. According to the UICC stage, there were 14 T1/T2 N3, 60 T3/T4 with among them 45 N3, and they were all MO. Comparisons were made through sequential closed plans. The combination chemotherapy was more efficacious than DDP with a difference that could be appreciated by the sequential analysis as high as 60% (95% confidence interval, 38% to 82%). The high-level toxicity appeared more significant (+25%) for the association. After radiation therapy 11 of 37 patients (30%) achieved a complete response in the arm with DDP versus 18 of 37 (49%) in that with DDP + FU. The median survival times were 9 and 11.5 months, respectively, and were not statistically different.