Objective To identify proteins differentially expressed between recurrent nasopharyngeal carcinoma(NPC) and non-recurrent NPC. Method Serum was collected from 20 patients with recurrent NPC and 20 patients with non-recurrent NPC. We used tandem mass tag labeling and high performance liquid chromatography fractionation,followed by liquid chromatography-tandem mass spectrometry to identify differentially expressed proteins. Candidate proteins were confirmed by ELISA in a separate set of serum samples comprising 40 patients with recurrent NPC and 41 with non-recurrent NPC. Results A total of 635 protein groups were identified in human serum,and expression levels of 413 proteins were quantified. In two independent tests with different subgroups of patients,41 proteins were found to be down-regulated and 18 to be up-regulated in recurrent disease. ELISA confirmed that A2M was down-regulated in 23 patients with recurrent disease compared to 30 with non-recurrent disease. (Other patients had A2M levels below the detection threshold of the ELISA). Spearman analysis showed that A2M concentration did not correlate with clinical stage (r =-0.024,P=0.866) or age(r =-0.087,P=0.534). Conclusion A2M expression may protect against risk of NPC recurrence and so may be a useful prognostic marker.