Fifty patients with histologically proven squamous-cell carcinoma of the head and neck, recurrent after surgery and/or radiation therapy, were treated with a triple-drug combination of methotrexate (MTX), 250 mg/m2 intravenously (IV) on day 1, followed by 5-fluorouracil (5-FU), 600 mg/m2 IV on days 1 and 2, followed by cisplatin, 50 to 60 mg/m2 IV on days 3 and 4. Patients were randomly assigned to receive cisplatin either in 300 mL of 3% saline or with standard mannitol diuresis along with appropriate hydration. The courses of treatment were repeated every 3 to 4 weeks. Among 47 evaluable patients, there were four complete responses (CRs) and 17 partial responses (PRs) (9% and 36%, respectively). The median duration of response was 23 weeks and the overall survival was 7 months. The median survival of responders v nonresponders was 12 months and 6 months, respectively. Nausea and vomiting was experienced by all patients and diarrhea was experienced by 36% of patients. Neutropenia occurred in 37 patients (79%) and resulted in fever or infection in 11 patients (23%) and death in two patients. Mild renal failure (persistent serum creatinine greater than 1.5 mg/ dL) was observed in ten patients (21%), six treated with 3% saline and four treated with mannitol. The median cumulative dose of cisplatin that lead to the development of renal impairment was 485 mg/m2 in the hypertonic saline arm and 550 mg/m2 in the mannitol arm (P = .40). The antitumor activity of this regimen was not superior to that of sequential MTX and 5-FU. The use of hypertonic saline was not effective in reducing the renal toxicity of cisplatin.