From January 2018 to May 2018, 108 patients with thoracic esophageal cancer underwent esophagectomy with two- to three-field lymph node dissection. Serum cytokeratin 19 fragment antigen 21-1 (CYFRA21-1), squamous cell carcinoma antigen, and carcinoembryonic antigen levels were detected before surgery. Preoperative serum levels of CYFRA21-1 and squamous cell carcinoma antigen were correlated closely with pN stage (P = 0.000 and P = 0.045). CYFRA21-1 and pathological T status were independent predictors of lymph node metastasis (P = 0.000). The area under the curve values of CYFRA21-1 and squamous cell carcinoma antigen for predicting lymph node metastasis were 0.731 (P =0.000) and 0.650 (P =0.007), respectively. Our study demonstrated that serum CYFRA21-1 and squamous cell carcinoma antigen levels were associated with lymph node metastasis in esophageal squamous cell carcinoma, especially in patients at the early T stage. The preoperative serum CYFRA21-1 level was an independent predictor of lymph node metastasis.