Colorectal cancer (CRC) is the most common type of gastrointestinal cancer and has three major pathways of carcinogenesis. About 80% of genomic instability concerns chromosomal instability (CIN); the rest is connected with either microsatellite instability (MSI) or CpG island methylation. Some MSI-related cancers are associated with Lynch syndrome, whereas others are caused by sporadic, acquired hypermethylation of the promoter of the MLH1 gene. These tumours have distinctive clinical and histopathological features. They may be poorly differentiated, accompanied by Crohn's-like lymphocytic infiltration and have a pushing margin. MSI-high (MSI-H) phenotype has a slightly better prognosis. We investigated 46 classic CRCs using histochemical and immunohistochemical methods (p53, MLH1, MSH2, MSH6). Based on the results, we divided patients into 4 groups. Tumours from the first and second group (27 cases) expressed the loss of MSI markers and presented a characteristic clinical and morphological image. The other 19 cases lacked significant immunohistochemical or microscopic features. These require further molecular studies to evaluate their carcinogenesis. Discovery of MSI in colorectal tumours should be taken into account in the management of patients. They do not respond to 5-fluorouracil or anti-EGFR therapy, especially the sporadic ones with BRAF mutations.