Background: Colorectal cancer is a significant cause of morbidity and mortality worldwide. As a result of this wide distribution of CRC, the disease carries a substantial financial burden on health systems, especially if it is detected in its advanced later stages. Application of the simple colorectal cancer screening through stool test (FOBT) has dramatically reduced the incidence of colorectal cancer in recent years. Aim of the study: The primary objective of the study is to evaluate the accuracy of a combination of stool tests (Enzyme Biomarker M2-PK and Immunological Faecal Occult Blood Test) in detecting advanced adenomas and colorectal adenocarcinomas. The study also aims to determine the usefulness of this combination of tests in screening programs. Another goal of the research is to compare the detection rates of advanced adenomas and colorectal adenocarcinomas between these two tests. Methods: The study included 94 patients recruited from a pool of 117 individuals undergoing routine colonoscopy screening. The indications to perform Colonoscopy must be other than study. Participants provided consent and completed study questionnaires. Stool samples were collected before colonoscopy preparation and sent by mail. Exclusions initially consisted of 19 participants who underwent only one screening method and four patients with chronic inflammatory bowel disease. Results: A total of 94 patients participated in the study. The sensitivity, specificity, and the negative predictive value (NPV) of the combination of tests (iFOBT and M2-PK) were calculated using the cut-off levels recommended by the manufacturer, which were ?25 µg Hb/g for iFOBT and > 4 U/ml for M2-PK stool test. Lowering the cut-off values for both tests in a combined test (ScheBo® • M2-PK + Hb™ (2in1 ELISA Stool Test) increased the sensitivity 64.4% but decreased the specificity to 56.36 %. Conclusion: The combination of the M2-PK Stool test and the Immunological Faecal Occult Blood Test (iFOBT) has shown potential and is a viable option. To benefit from the combination, we suggest decreasing of the cut-off levels of both tests. However, additional extensive research is required to determine the full benefits of this combination as a screening tool for colorectal cancer.Colorectal cancer is a significant cause of morbidity and mortality throughout the world. Beyond the devastating humanitarian impact of the CRC, the economic impact on healthcare systems is substantial. Most cases of CRC are sporadic. Both genetic and environmental factors contribute to the pathogenesis of colorectal cancer. To reduce the morbidity and mortality of CRC, there is a continuous and endless search for an optimal screening test. Colonoscopy is considered the gold standard of colorectal cancer screening. Unfortunately, colonoscopy does not have broad acceptance among patients. Non-invasive screening tools such as computer tomographic colonography, MRI colonography, colon capsule endoscopy, and many stool tests are still under validation. The stool tests present an easy and convenient screening for patients and health systems. The significant variation in sensitivity and specificity of stool tests is considered the main difficulty in validating and approving the tests in screening for colorectal cancers. In the past, the Guaiac-based faecal occult blood tests (gFOBT) were crucial in detecting colorectal cancer. However, its limitations in use as a screening tool and the need for specific dietary restrictions prompted the creation of a new type of stool test, the Faecal immunochemical test (IFOBT), which tests for antibodies against globin. The concept of combining two tests, each relying on different principles, is a novel idea and numerous studies have been conducted to evaluate the potential benefits of such a combination. Aiming to find a sensitive non-invasive diagnostic tool for colorectal cancer, we designed this multicenter study comparing M2PK with iFOBT. We also looked at how efficiently the two tests performed together, utilizing the M2PK's higher sensitivity and the IFOBT's higher specificity. According to the available literature, the results indicate that M2-PK stool tests have a sensitivity of 79% and a specificity of 80% when using a cut-off value of 4 U/ml. This gives the M2-PK test a higher sensitivity compared to the FOBT, but a lower specificity in comparison (Uppara et al., 2015). Based on these results, studies suggested incorporating M2-PK into screening process for bowel cancer alongside iFOBT or other stool tests. Many studies have shown the benefits of using both M2PK and iFOBT tests together. For example, the study conducted by Prenete et al. in multiple centers found that combining these tests was effective in identifying patients who need colonoscopy based on a positive result from the iFOBT test (Parente et al., 2012a). Determining the optimal cut-off: The study also focused on examining the impact of modifying the cut-off levels. With regards to the tumor M2-PK, when using a cut-off level of 4 U/ml (as recommended by the manufacturer), the sensitivity for detecting colorectal polyps was found to be 37.84 (95% CI: 22.5-55.2), which was higher compared to the sensitivity of iFOBT (ScheBo Hb Smart™ ELISA) using a cut-off level of 25 U/ml (as recommended by the manufacturer), which was 21.62% (95% CI: 9.8-38.2). The specificity of tumor M2-PK in identifying colorectal polyps was estimated to be 75.44 (62.2-85.9), which was slightly lower compared to the specificity of iFOBT, which was 77.19 (64.2-87.3). Modifying the cut-off levels of either test in the combination could result in a positive effect on the adenoma detection rate (ADR): With a Tumor M2-PK stool test cut-off level of 2.45 U/ml, the sensitivity for polyps increased to 70.27 (95% CI: 53.0 - 84.1), but the specificity decreased to 22.81 (95% CI: 12.7 - 35.8), which is markedly lower than that of iFOBT, which is 77.19 using a cut off ?25 µg Hb/g (as recommended by the manufacturer). The Faecal M2-PK test cannot replace the faecal immunochemical test (IFOBT) in predicting the risk of neoplastic lesions in screening programs. Both tests can offer a potential screening tool for detecting non-bleeding adenomas and cancers. To prove this potentiality, we require large-scale studies to test the benefit of such a combination in reducing hospital waiting lists for a screening colonoscopy.