The purpose of this study was to investigate clinical-biological factors which could predict the sensitivity to chemoradiotherapy of esophageal squamous cell carcinoma (ESCC). One hundred eighty-one patients with stages I-IV ESCC were evaluated. The cytokeratin 19 fragment antigen 21-1 (CYFRA21-1), carcinoembryonic antigen (CEA), albumin (A) as well as hemoglobin (HB) concentration were measured before the initiation of chemoradiotherapy (CRT). The cutoff values of CYFRA21-1, CEA, and A were defined as 3.4 ng/ml, 3.3 ng/ml, 3.5 g/dl, respectively. HB was divided into three levels: <12.0, 12.0-14.0, and >14.0 g/dl. Clinical factors such as sex, age, tumor location, primary cancer length, and tumor-node-metastasis stage were also evaluated. The effective rate (complete response + partial response) of the primary tumor estimated by computed tomography was 60.71% (17 out of 28) in patients with CEA high group while 92.54% (62 out of 67) in patients with CEA low group (P = 0.000) and 62.50% (20 out of 32) in patients with CYFRA21-1 high group while 92.98% (53 out of 57) in patients with CYFRA21-1 low group (P = 0.000). HB levels before and during CRT were also associated with the effectiveness (P = 0.005, 0.033, respectively). HB levels before CRT at 12.0-14.0 g/dl were associated with the best effectiveness, followed by >14.0 and <12.0 g/dl (effective rates 88.89% vs. 83.75%, 62.07%, respectively, P = 0.005). HB levels during CRT also showed similar results (effective rates 87.80% vs. 85.41%, 70.59%, respectively, P = 0.033). Furthermore, according to numbers of the above risk factors, the sensitivity of CRT was higher in patients with zero to one risk factors than those with two to four risk factors (P = 0.023). CYFRA21-1 and CEA as well as HB and their combination may be helpful in predicting the sensitivity to CRT of ESCC. However, the results should be further confirmed in larger, more homogeneous studies.