Objective To compare the colonoscopy results of patients with positive fecal SDC2, ADHFE1, and PPP2R5C gene methylation tests to those with positive fecal occult blood tests, and analyze the effectiveness of colorectal cancer (CRC) screening. This study aims to provide a scientific basis for risk assessment in CRC screening.Methods From December 2023 to May 2024, 9 284 combined test kits for SDC2, ADHFE1, and PPP2R5C gene methylation were distributed to high-risk individuals aged 40 ~ 80 years. Among them, 841 patients (9.1%) tested positive. These patients were encouraged via telephone to undergo colonoscopy, with colonoscopy combined with pathological diagnosis as the gold standard, a total of 495 positive patients completed electronic colonoscopy. Among them, the 251 patients who tested positive for fecal SDC2, ADHFE1, and PPP2R5C gene methylation and completed electronic colonoscopy were the observation group; concurrently, 244 patients who tested positive for fecal occult blood tests and underwent electronic colonoscopy were selected as the control group. Compare two groups of patients with polyp, number, shape, pathological changes and pathological types.Results There was no statistically significant difference in number and lesion location of polyps between the two groups of patients (P > 0.05). The proportion of Yamada type I in the observation group was lower than that in the control group, while the proportion of Yamada type II was higher than that in the control group. The difference was statistically significant (P < 0.05). In the observation group, 1 case (0.4%) of CRC, 62 cases (24.7%) of advanced adenomas, 78 cases (31.1%) of non-advanced adenomas, 20 cases (8.0%) of hyperplastic polyps, and 90 cases (35.9%) with no dysplastic lesions were identified. In the control group, 6 cases (2.5%) of CRC, 38 cases (15.6%) of advanced adenomas, 53 cases (21.7%) of non-advanced adenomas, 19 cases (7.8%) of hyperplastic polyps, and 128 cases (52.5%) with no dysplastic lesions were identified. The proportions of non-advanced adenomas and advanced adenomas were lower in the control group than those in the observation group, while the no dysplastic lesions rate was higher in the control group, the differences were statistically significant (P < 0.05).Conclusion The detection rate of colorectal non-advanced adenomas and advanced adenomas is higher with fecal SDC2, ADHFE1, and PPP2R5C gene methylation testing compared to the fecal occult blood test.