We investigated if the serum cytokeratin 19 fragment 21.1 (CYFRA21-1) level was elevated in nasopharyngeal carcinoma (NPC) and can function as a biomarker for detection and monitoring of NPC. Three hundred and one study subjects were divided into two groups: the NPC group (n=126) and healthy control group (n=175). Serum CYFRA21-1 levels were measured before and after treatment using a chemiluminescent immunoassay, and its association with tumor stage and the clinical objective responses were analyzed. Receiver operating characteristic (ROC) curve analysis was performed to discriminate patients with NPC from the healthy controls. The pretreatment serum CYFRA21-1 level was significantly elevated in patients with NPC compared with the healthy controls (5.07±1.98 ng/ml vs 2.36±1.21 ng/ml, p<0.001), and it declined significantly after the entire treatment (2.14±0.72 ng/ml, p<0.001). The serum CYFRA21-1 level of patients with a classification of T3-4 was significantly higher than that of those with class T1-2 (5.64±2.23 ng/ml vs 4.62±1.64 ng/ml, p=0.006), and that of patients with clinical stage III-IV was higher than clinical stage I-II (5.31±2.02 vs 4.04±1.37 ng/ml, p=0.003). The AUC, sensitivity and specificity of elevated serum CYFRA21-1 in patients with NPC was 0.91, 0.83 and 0.89 respectively. In conclusion, the serum CYFRA21-1 level could be a reliable and effective biomarker for the detection and monitoring of NPC tumor progression.