Twenty-one chemotherapy-naive patients with unresectable or metastatic squamous cell carcinoma of the head and neck (SCCHN) received a combination chemotherapy including cisplatin (CDDP), methotrexate (MTX), folinic acid (LFA) and 5-fluorouracil (5-FU). The doses of the 3 cytotoxic drugs were escalated until dose-limiting toxicity occurred in more than 1/3 of the patients. The treatment was generally well tolerated; no toxic deaths occurred. Only 2 patients showed dose-limiting neutropenia. Non-haematologic drug toxicities were infrequent and never reached grade 3. 3/21 (14%) complete responses and 6/21 (29%) partial responses were observed, for an overall response rate of 43%. 5/6 patients treated at step 5 achieved an objective response to treatment and 2 complete responses were observed in this group of patients. Although maximum tolerated doses (MTD) were not reached even at step 5, we decided to stop the escalation and to recommend this level for the phase II study. Our regimen combines a good tolerability with a high level of activity at step 5; a phase II study is currently ongoing.