Objective To explore differential expression of protiens between patients with esophageal cancer and healthy individuals, and to screen out the tumor biomarkers to construct a dignostic model. Methods From January to August, 2008, the clinical data of 127 patients with esophageal cancer (esophageal cancer group) who had been admitted to the First Affiliated Hospital of Xinjiang Medical University and 63 healthy individuals (control group) were retrospectively analyzed. The serum proteomic profiles of the esophageal cancer pateints and healthy individuals were deteced by weak cation exchange and hydrophobic surface ProteinChip using the surface enhanced laser desorption/ionization-time of flight-mass spectrometry (SELDT-TOF-MS) technique.Serum differentially expressed markers of esophageal cancer were screened out to establish the diagnostic model for esophageal cancer. All data were analyzed using rank sum test. Results Six proteins were high-expressed in the esophageal cancer group, and the mass-to-charge ratios were 4488, 5495, 15964, 3948, 8154, 8166. Four were low-expressed in esophageal cancer group, and the mass-to-charge ratios were 8789, 6682, 8714, 6650. A diagnostic model consisting six proteins was established. A total of 124 patients were correctly diagnosed and three were misdiagnosed in the esophageal cancer group, and 60 were correctly diagnosed and three were misdiagnosed in the control group. The accuracy, sensitivity and specificity of the diagnostic model were 96.8% ( 184/190),97.6% ( 124/127 ) and 95.2% (60/63). Conclusions The diagnostic model established based on the tumor markers screened out by the SELDT-TOF-MS is highly sensitive and specific.