Patients with esophageal small cell carcinoma undergoing definitive chemoradiotherapy (CRT) seem to have disparity in tumor response. The identification of CRT sensitivity-related tumor markers would be helpful for selecting patients most likely to benefit from CRT. The aim of this study was to examine the predictive value of biological markers in small cell carcinoma of the esophagus (SCEC) patients treated with definitive CRT. Pretreatment serum levels of neurone-specific enolase (NSE), cytokeratin 19 fragment antigen 21-1 (CYFRA21-1), and carcinoembryonic antigen (CEA) were measured by immunoradiometric assays, while the tumor responses were evaluated according to the World Health Organization response criteria. The relationships between pretreatment expression of NSE, CYFRA21-1, CEA, and the tumor response to CRT were analyzed. The effective rates (complete response + partial response) in NSE high and low groups were 10.80 % (9/82) and 37.98 % (31/82), respectively (P = 0.003).The results from statistical analysis indicated that the effectiveness of CRT was significantly associated with the serum levels of NSE before treatment (P = 0.002). The overall survival (OS) of the patients with high NSE levels was worse than that of those with low NSE levels (P = 0.004). In multivariate analysis, low level of NSE was the most significant independent predictor of good OS (P = 0.003). The result showed a promising predictive value of NSE regarding to the sensitivity of tumors to CRT. NSE may be a reliable surrogate marker of CRT efficacy in patients with SCEC.