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Qiang Zhao,1 Congxiu Miao,2 Qingpu Lu,1 Weipeng Wu,1 Yuan He,1 Shouxin Wu,3 Huimin Liu,3 Changhong Lian1 1Department of Gastrointestinal Surgery, Heping Hospital, Changzhi Medical College, Changzhi, 046000, Shanxi, People’s Republic of China; 2Department of Science and Technology, Changzhi Medical College, Changzhi, 046000, Shanxi, People’s Republic of China; 3Biotecan Medical Diagnostics Co., Ltd., Zhangjiang Center for Translational Medicine, Shanghai, 201203, People’s Republic of ChinaCorrespondence: Changhong Lian; Huimin Liu Tel +8613835550029; +8613818196591Email lianchanghong0029@163.com; benbendelhm@163.comBackground: Esophageal squamous cell carcinoma (ESCC) is the predominant histological type of esophageal cancer in China and has an extremely poor prognosis. Circulating free DNA (cfDNA) and plasma heat shock protein 90alpha (Hsp90a) are two novel noninvasive biomarkers for diagnosis and prognostic prediction of several types of cancer. However, to the best of our knowledge, the roles of the two biomarkers in ESCC are still unknown.Methods: Here, we recruited 93 primary ESCC patients and detected plasma concentrations of the two markers at different time points, including 1– 3 days pre-chemotherapy, 1– 7 days pre-surgery and 7– 14 days post-surgery. Baseline concentrations of the two markers were associated with main characteristics of ESCC patients which were collected at first diagnosis. Correlation between the two markers and traditional serum biomarkers at baseline was also examined. Furthermore, dynamic changes of the cfDNA and Hsp90α concentrations among different time points and the potential clinical significance were assessed.Results: Consequently, there was no significant association between baseline concentrations of the two markers and clinical features. Especially, cfDNA demonstrated stronger correlation with other circulating biomarkers than Hsp90α at baseline level. Importantly, both cfDNA and Hsp90α concentrations were significantly increased after surgery. Kaplan–Meier survival analysis showed that a change in concentration of cfDNA (ΔcfDNA) but not Hsp90α (ΔHSP90ɑ) between pre-surgery and post-surgery had significant effect on the overall survival of surgical patients with ESCC.Conclusion: Thus, ΔcfDNA evaluation could be a promising prognostic marker for surgical ESCC patients. Our findings may improve the understanding of the function of cfDNA and Hsp90α in ESCC.Keywords: esophageal squamous cell carcinoma, circulating free DNA, heat shock protein 90alpha, prognostic marker