Objective To explore the value of methylation of SDC2 and SFRP2 genes promoter in fecal DNA for colorectal cancer (CRC) screening. Methods All stool samples were enrolled from Changhai Hospital of Naval Medical University, the Tenth People′s Hospital of Tongji University and the Seventh Medical Center of Chinese People′s Liberation Army General Hospital. A total of 500 stool samples collected from March 2018 to December 2018 were allocated to CRC group (132 CRCs), adenoma group (38 advanced adenomas), healthy group (152 healthy individuals), interferential group (178 cases of benign colorectal disease or other non-colorectal tumors) and negative group (330 cases composed of healthy group and interferential group). The promoter methylation of fecal SDC2 and SFRP2 genes was detected by methylation-specific PCR (MSP) and compared with single gene methylation and the fecal immunochemical tests (FIT) to evaluate its sensitivity and specificity. Results The stool sample analysis showed that the sensitivity of combined detection of SDC2 and SFRP2 in CRC group was 97.73% (129/132)，which was significantly higher than those of the single gene SDC2 test [70.45% (93/132), P=0.000], single SFRP2 test [81.82% (108/132), P=0.000] and FIT [69.70% (92/132), P=0.000]. In adenoma group, the sensitivity of combined detection of SDC2 and SFRP2 was 57.89% (22/38), which was significantly higher than those of the single gene SDC2 test [15.79% (6/38), P=0.000] and FIT [21.05% (8/38), P=0.021], with no significant difference compared with that of SFRP2 test [47.37% (18/38), P=0.358]. In healthy group, the specificity of combined detection of SDC2 and SFRP2 was 98.68% (150/152), with no significant difference compared with those of single gene SDC2 test [100.00% (152/152), P=0.156], single SFRP2 test [98.68% (150/152), P=1.000] or FIT [95.39% (145/152), P=0.091]. Specificities of combined detection of two genes in interferential and negative groups were 90.45% (161/178) and 94.24% (311/330), which were significantly higher than 73.03% (130/178, P=0.000) and 83.33% (275/330, P=0.000) of FIT, respectively. Conclusion The combined detection test of methylation of SDC2 and SFRP2 is superior to single gene test, whose sensitivity of CRC and aggressive adenoma and specificity of distinguishing benign and malignant lesions are higher than FIT, which has potential application value.