BACKGROUND Systemic disease progression occurs in the majority of patients with locally advanced nasopharyngeal carcinoma (NPC). Although a variety of chemotherapeutic drugs have had tumoricidal activity, the roles of chemotherapy and optimal regimens must be further defined. Based on high response rates of Cisplatin, 5-Fluororacil and Leucovorin (PFL) in patients with advanced squamous cell cancers of the head and neck, we tested a new outpatient PFL chemotherapy program in patients with advanced NPC. METHODS Patients with NPC and 1) previously untreated, locally advanced disease; 2) local regional recurrence (LR) after radiotherapy; or 3) metastatic disease were eligible for study. Cisplatin 20 mg/m2/d, 5-FU 800 mg/m2/d and Leucovorin 90 mg/m2/d were administered simultaneously by continuous 96-hour intravenous infusion every three weeks. Patients were evaluated for response, survival, and toxicity. RESULTS Thirty-five patients were studied. The response rates of PFL therapy were 100% (15% complete response [CR], 85% partial response [PR]) in 20 patients with locally advanced or locally recurrent disease, and 80% (13.3% CR, 67.7% PR) in 15 patients with metastatic disease. The overall median survival was 20 months after therapy (range, 2-21). The median survival rate for previously untreated, locally advanced patients was not reached. The median survival rate for previously treated, local recurrence was 34 months and for metastatic patients was 14 months. Mucositis and leukopenia were the dose-limiting toxicities (20-23%, grade III) and occurred more frequently in patients previously irradiated. No treatment-related deaths occurred. CONCLUSIONS Outpatient PFL chemotherapy is active, safe, and convenient for advanced stage nasopharyngeal carcinoma patients, and the overall toxicities are tolerable.