Aim of the study - To detect hereditary non-polyposis colorectal cancer (HNPCC) patients with a strategy com-bining clinical selection (patient age at onset of cancer less than 50 years or family history of HNPCC tumors) and microsatellite instability typing plus immunohistochemistry, leading to mismatch repair (MMR) germline mutation analysis. Methods - Tumors were screened for microsatellite instability (MSI) and for hmlh1 and hmsh2 immunohistochemical expression. Germ-line mutation an-alysis was performed to search for MLH1 and MSH2 mutations in patients with MSI-High and MSI-Low tumors. Results - 197 adenocarcinomas were studied: 164 patients were ≤ 50 years old, 33 were older than 50 years but had a family history of HNPCC tumors. Fifty tumors (25.4% ) were MSI-High, 10 were MSI-Low (5.1% ), and 130 were MS- Stable (66% ). MSI typing was inconclusive in 7 (3.5% ). Immunohistochemistry screening was performed on 165 tumors: sensitivity was 63.6% , specificity was 99% . Germline mutation analysis was performed in 33/60 MSI-High or Low tumors: 23 mutations were noted (70% of the tested patients). Conclusion - This proposed strategy of determining microsatellite instability in young colorectal cancer patients or in patients with a family history of HNPCC tumors led to an increased frequency in the detection of MMR germline mutations. Aim of the study - To detect hereditary non-polyposis colorectal cancer (HNPCC) patients with a strategy com-bining clinical selection (patient age at onset of cancer less than 50 years or family history of HNPCC tumors) and microsatellite instability typing plus immunohistochemistry, Methods - Tumors were screened for microsatellite instability (MSI) and for hmlh1 and hmsh2 immunohistochemical expression. Germ-line mutation an-alysis was performed to search for MLH1 and MSH2 mutations in patients with MSI Fifty tumors (25.4%) were MSI-High, 10 and were older than 50 years but had a family history of HNPCC tumors. MSI typing was inconclusive in 7 (3.5%). Immunohistochemistry was performed on 165 tumors: sensitivity was 63.6%, specificity was 99%. Germline (5.1%), and 130 were MS-Stable m utation analysis was performed in 33/60 MSI-High or Low tumors: 23 mutations were noted (70% of the tested patients). Conclusion - This proposed strategy of determining microsatellite instability in young colorectal cancer patients or in patients with a family history of HNPCC tumors led to an increased frequency in the detection of MMR germline mutations.