We investigated the predictive value of decline in the serum levels of tumor markers on tumor response during the chemoradiotherapy (CRT) in patients with non-small cell lung cancer (NSCLC). The serum levels of cytokeratin 19 fragment antigen 21-1 (CYFRA21-1), neurone-specific enolase and carcinoembryonic antigen were measured by enzyme-linked immunosorbent assays, while the tumor responses were assessed according to the World Health Organization response criteria. The relationship between the changes of serum level of tumor markers and the radiologic response were analyzed. The effective rates (CR + PR) in CYFRA21-1 (pretreatment serum level) high and low groups were 45.8% (33/72) and 66.7% (24/36), respectively (p=0.032). Independent sample t test showed that the relationship between the response of CYFRA21-1 and the radiologic objective response are significantly different (p=0.008). The best cutoff value of the decline ratio of CYFRA21-1 was established as 18.48% by ROC curve. CYFRA 21-1 responses appeared to be reliable surrogate markers to predict chemoradiotherapy efficacy in patients with NSCLC, an average drop of 18.48% in serum CYFRA21-1 appears to provide the predictive information for the sensitivity of CRT.