Objective To evaluate the diagnostic value of combined detection of serum CEA, CA19-9, cell keratin fragment 19 (CY211) and CK to distinguish colonic polyps and colon cancer. Methods The serum levels of CEA, CA19-9, CY211, and CK were detected in the colon polyps and colon cancer,and control group. The binary logistic regression analysis was used for analyze the diagnostic value of combined detection of four markers. Results The serum CEA and CA199 levels in colon cancer were significantly increased than that of colon polyps group (P＜0.05), but the serum CK in colon cancer was significantly decreased(P＜0.05). When the four indicators were used alone to distinguish between colon polyps and colon cancer patients, CEA showed the best diagnostic value in the four indicators, the area under curve was 0.728. The diagnostic sensitivity and specificity with CEA were 54.9% and 91.4% respectively. When combined detection of CEA, CA199, CY211, and CK, the area under curve was 0.847. The diagnostic sensitivity and specificity were 73.6% and 85.5% separately. Conclusion The combined detection of CEA, CA19-9, CY211, and CK could increase the sensitivity and specificity in the clinical diagnosis of colon cancer.