Objectives To investigate the value of serum cytokeratin 19 fragment (CYFRA21-1), carbohydrate anti-gen 19-9 (CA19-9) and squamous cell carcinoma antigen (SCCAg) in the diagnosis of esophageal cancer. Methods 100 cases of esophageal cancer (study group) and 50 healthy subjects (control group) were recruited in the study, the serum levels of CYFRA21-1, CA19-9 and SCCAg in these patients were detected. Subgroups analysis was performed in study group by clinical staging, and the diagnostic value of CYFRA21-1, CA19-9 and SCCAg in detecting esophageal cancer was analyzed by receiver operating characteristic curve (ROC). Results The serum levels of CYFRA21-1, CA19-9 and SCCAg in study group were significantly higher than those in control group, and those were significantly lower in patients with stageⅠ-Ⅱ disease than those with stage Ⅲ and Ⅳ disease, indicating statistically significant difference (P<0.01); the sensitivity of serum CYFRA21-1, CA19-9 and SCCAg in the diagnosis of esophageal cancer was 82.26%, and specificity was 91.33%,  with positive predictive value being  86.14%, and negative predictive value being 89.57%, and AUC value was 0.864, the combined detection was superior to each measure utilized alone, the difference was significantly significant (P<0.05). Conclusion The combined detection of serum CYFRA21-1, CA19-9, and SCCAg can significantly improve the diagnostic sensitivity and specificity in detecting the esophageal cancer.