One of the most active chemotherapeutic regimens for treatment of advanced and recurrent head and neck cancer is cisplatin (CACP) + 5-fluorouracil (5-FU) infusion with a response rate of 90% in advanced, previously untreated patients and 70% in patients with recurrent disease. Forty-four patients from two Wayne State University-affiliated hospitals were entered into a randomized trial of CACP (100 mg/m2) day 1 and 24-hour infusion of 5-FU (1000 mg/m2) days 1 through 4 versus CACP (100 mg/m2) day 1 and bolus 5-FU (600 mg/m2) day 1 and day 8. Thirty-eight patients were evaluable for three induction courses. Response for the infusion arm was 72% (4/18 complete response [CR] + 9/18 partial response [PR]). Response for the bolus arm was 20% (2/20 CR + 2/20 PR). The difference in response was statistically significant by chi-square analysis (P less than 0.01). Seventy percent of the patients on the bolus arm experienced leukopenia with several episodes of grades 3 and 4 leukopenia. In addition, 50% of the patients on the bolus arm experienced thrombocytopenia. Stomatitis was more frequent on the infusion arm but it was mild and reversible. The complete responders on either arm have a median survival of 120+ weeks; partial responders, 30 weeks. Cisplatin + 5-FU infusion produces a superior response as initial chemotherapy for three courses compared with CACP and 5-FU bolus.