Microsatellite instability (MSI) influences the development and clinical course of colorectal cancers (CRCs) and induce specific morphological alterations of such neoplasms, therefore hematoxylin-eosin (H&E) based histology allows to predict the microsatellite status of a given tumor. The aim of this article is to demonstrate clinicopathological features that are useful in recognition of microsatellite-stable and -unstable CRCs on routine histological examination. In the Center of Surgical and Molecular Pathology of National Institute of Oncology, from 384 CRC cases 26 hereditary non-polyposis colorectal cancers (HNPCC), 22 sporadic high-level microsatellite-instable (MSI-H) cancers and 76 microsatellite-stable (MSS) or low-level MSI (MSI-L) CRCs were selected on the basis of the localization, clinical stage, microsatellite status, and patient age at the time of the diagnosis. Our results showed that we can recognize MSS/MSI-L carcinomas, HNPCCs and sporadic MSI-H tumors with high probability on the base of clinicopathological features like patient's age, tumor localization, clinical stage and histological characteristics of CRCs, even if the genetic MSI test is not available. The main morphological characteristics related to microsatellite instability are intratumoral or stromal infiltrating lymphocytes/leukocytes, large, vesicular nuclei with prominent nucleoli, and expansive infiltrative edge of the tumors. Careful and detailed morphological analysis of colorectal cancers helps to select the appropriate molecular method to determine the molecular features that influence the clinical care of patients and allow to consider the most appropriate anti-tumor therapy.