Background: Nasopharyngeal carcinoma (NPC) is a chemo-sensitive disease but there is yet no consensus on the best regimen for recurrent or metastatic diseases. Pemetrexed is a new agent with good efficacy and toxicity profiles in other cancers. This phase II study aims to evaluate its use in combination with cisplatin for NPC. Methods: Patients (pts) with metastatic or extensive recurrence (unsuitable for radical surgery or re-irradiation) were included. All had prior treatment with platinum-based chemotherapy. The regimen consisted of pemetrexed 500mg/m² (with vitamin B12 and folic acid support) and cisplatin 75mg/m² every 3 weeks. Assessments of efficacy were based on both radiological and biochemical (DNA copies of Epstein-Barr virus) response. Toxicity profile was assessed by both acute toxicity rates and quality of life (QOL) scores (measured with FACT-H&N version 4). Patients with response/stable disease and good tolerance were given another 2-4 cycles. Results: Fourteen pts (5 with loco-regional recurrences and 9 with metastases) were treated with this regimen; their median age was 51 (range, 39-68) years. All except one pts had elevated EBV-DNA (median, 34,750 copies/ml; range, 42–17,500,000). A total of 4-8 (median, 6) cycles had been given. Reduction of EBV-DNA copies by >=50% was observed in 12/13 (92%) pts, 2/13 (15%) pts even achieved biochemical complete remission (CR). Radiological assessment showed that one (7%) pt achieved CR, 2 (14%) had partial remission and 7 (50%) had stable diseases. The median time to progression was 30 weeks (range, 11-119 weeks). Only one pt (7%) developed grade 4 toxicity (anemia). The most common grade 3 toxicities were neutropenia (29%) and anemia (21%). All 14 pts had QOL assessment at baseline and after the fourth cycle; 12 (86%) pts had further assessment after the sixth cycle. No significant deterioration in QOL was observed: the total QOL scores (mean) changed from 99 at baseline to 95 after the fourth cycle (p=0.35) and 90 after the sixth cycle (p=0.16). Conclusions: Cisplatin-pemetrexed was a well tolerated regimen and the efficacy for metastatic/recurrent NPC was encouraging. Further evaluation of its role in treatment of NPC is warranted.