Abstract: Objective To compare the clinical efficacy and toxicity of nolatrexed plus cisplatin （LP regimen） versus fluorouracil plus cisplatin （FP regimen） in the treatment of metastatic nasopharyngeal carcinoma（NPC）. Methods Thirty-three cases of metastatic NPC patients from October 2005 to March 2011 were collected and randomly divided into LP regimen and FP regimen according to 1∶1. Sixteen patients and seventeen patients were treated with LP regimen and FP regimen， respectively. LP regimen：nolatrexed 740mg／m2 civ 120h d1-d5；cisplatin 25mg／m2 iv d2-d4；FP regimen：fluorouracil 600mg／m2 civ 120h d1-d5; cisplatin 25mg／m2 iv d2-d4.The two regimens were repeated every three weeks and lasted for 2 to 6 cycles. Results The response rate，disease control rate，the median time to progress and the median overall survival of LP regimen and FP regimen were 31.3％ and 35.3％， 68.8％ and 76.5％， 3.4 months and 3.8 months，and 9.5 months and 10.0 months without significance between the two regimens（P＞005）.Toxicity of the two regimens were mainly in grade 1-2，oral toxicity of LP regimen was significantly lower than that of the FP regimen （P＜0.05） and other toxicities between the two groups had no differences. Conclusion The efficacy of LP regimen is similar to that of FP regimen，but the oral toxicity of LP regimen is much lower than that of FP regimen. LP regimen is expected to become one of the first-line regimens for metastatic NPC.