Objective To evaluate the significance of serum colon cancer-specific antigen-2 （CCSA-2） in diagnosisof colorectal cancer （CRC）. Methods By using ELISA method， the serum CCSA-2 was measured from 105 patients with 5 kinds of diseases， including CRC， gastric cancer， inguinal hernia， acute appendicitis， and breast cancer， who weretreated in our hospital from Jul. to Dec. in 2008， and 20 health donors were enrolled in addition. The blood samples were collected on 3 days before surgery， but blood samples from patients with acute appendicitis were collected before emergencysurgery， blood samples of health donors were collected on 1 day before ELISA test. Results The level of serum CCSA-2 in CRC patients was （99.27±6.25） μg/L， which was significantly higher than those of other patients and health individuals〔（53.58±2.73） μg/L， t=48.29， P=0.000〕. Serum CCSA-2 at a cutoff of 73.96μg/L had a sensitivity of 100% （95% CI：100%-100%） and a specificity of 100% （95% CI：100%-100%） in separating CRC populations from all other indivi-duals by using receiver operator characteristic curve （ROC） analysis. As compared with carcinoembryonic antigen （CEA） and CA19-9， the serum CCSA-2 assay （at a cutoff of 73.96μg/L） was significantly more sensitive than CEA and CA19-9 assay in CRC detection （P＜0.01）. Serum CCSA-2 was not related with patients’ gender （P=0.81）， age （P=0.59）， TNM stage （P=0.85）， Dukes stage （P=0.63）， nuclear grade （P=0.44）， as well as expressions of multidrug resistance associated protein （P=0.33）， P-glycoprotein （P=0.72）， and topoisomeraseⅡ（P=0.95）， but higher in patients with colon cancer than those of patients with rectal cancer （P=0.02）. Conclusion Serum CCSA-2 may be a useful biomarker in diagnosis of CRC， and it may be only related to tumorigenesis， but is irrelated to tumor progression and chemotherapy.