In our study, 23 proteins, namely, ANXA1, hK8, CDKN1A, ABL1, SCAMP3, EGF, LYN, MetAP2, KLK13, ADAMTS15, hK14, VIM, TXLNA, GPC1, RSPO3, hK11, TRAIL, X5NT, CPE, FADD, TGFR2, SEZ6L and CD160, showed potential diagnostic utility for distinguishing early ESCC from controls and their serum levels showed a significant dose-response relationship with ESCC stages. Here, CDKN1A is linked to esophageal squamous cell carcinoma.