Current chemotherapeutic approaches to recurrent or metastatic head and neck cancer have yielded response rates of 10% to 20% for single agents and 30% to 40% for combination chemotherapy. Median survival for patients with recurrent or metastatic disease treated with single agents or combination chemotherapy is between 4 and 6 months. Investigation of new drugs, therefore, has high priority among clinicians and researchers. One new agent that has been effective as single-agent therapy is paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ). We tested the combination of paclitaxel, ifosfamide, and cisplatin in recurrent or metastatic head and neck cancer. The starting dose of paclitaxel was 175 mg/m2 as a 3-hour infusion on day 1, ifosfamide 1 g/m2 as a 2-hour infusion on days 1 to 3, and cisplatin 60 mg/m2 via 2-hour infusion on day 1. This schedule was repeated every 3 weeks. Sixty-five patients were entered into the study and 62 patients are currently evaluable for response and toxicity in the phase I and phase II portions of this study. We observed 10 (16%) complete responses and 24 (39%) partial responses. The overall response rate was 55% in phases I/II of this interim analysis. In the phase II part alone, we have observed eight (16%) complete responses and 22 (44%) partial responses to date among 50 evaluable patients. Median survival times were 8.9 months for all patients and 9.7 months for patients in the phase II part of the study. Preliminary results demonstrate significant antitumor activity in patients with recurrent or metastatic head and neck cancer. The paclitaxel/ifosfamide/cisplatin regimen was well tolerated. Chemotherapy with paclitaxel/ifosfamide/cisplatin should be tested as an induction regimen in patients with locally advanced head and neck cancer. It also warrants testing in a randomized setting to compare it with a standard regimen, such as the combination of 5-fluorouracil and cisplatin.