Eighty-three patients (median age, 56 years and Karnofsky performance status greater than or equal to 70) were treated with carboplatin (Carbo) and fluorouracil (5Fu) for stage III and IV head and neck squamous cell carcinoma (HNSCC). 5Fu (1 g/m2/d) was administered from day 1 to 4 by continuous infusion. Carbo was given on day 1 and, in order to evaluate its maximum-tolerated dose (MTD), the dose level was progressively increased from 250 mg/m2 to 450 mg/m2. The effectiveness of this association and its potential role in local control were also evaluated. Three patients received Carbo at a dose of 250 mg/m2, 13 received 300 mg/m2, one received 330 mg/m2, 12 received 350 mg/m2, six received 375 mg/m2, 26 received 400 mg/m2, 18 received 420 mg/m2, and four received 450 mg/m2. Two (13 of 83) or three courses (64 of 83), repeated every 4 weeks, were administered. The overall (primary tumor and node) response and complete response (CR) rates were 33% and 14%, respectively. For primary tumor, the response rate (RR) was 57% with 32% CR and 18% pathologic complete response (PCR); the RR was higher for patients with oropharyngeal tumor (76%, P = .037) and for patients treated with Carbo greater than or equal to 350 mg/m2 (65%, P = .02); the tumor size (T1 + T2 v T3 + T4) was a good prognostic factor for RR (90% v 46%, P = .001), CR (65% v 20%, P less than .001), and PCR (45% v 8%, P less than .001). For nodes, the RR was 33% with 11% CR. Grade 3-4 neutropenia and thrombocytopenia were experienced by 17% and 28% of the patients treated with 420 mg/m2 of Carbo and by 50% of the patients treated with 450 mg/m2. The MTD can be fixed at 420 mg/m2 and the proposed dose at 400 mg/m2. Thirty-eight patients were treated with surgery plus radiotherapy, 33 with radiotherapy alone, and seven with surgery alone. The median follow-up is 12 months. The 18-month disease-free survival (DFS) is 78% for overall complete responders and 39% for the others (P = .04). There is no primary tumor recurrence among the 12 patients with a primary tumor PCR treated by radiotherapy alone for tumor control (median follow-up, 17.3 months). The association of Carbo-5Fu is a safe induction chemotherapy regimen for HNSCC. The proposed dose of Carbo for future treatment is 400 mg/m2.(ABSTRACT TRUNCATED AT 400 WORDS)